Compounds for the prevention and treatment of cardiovascular diseases

The present invention relates to compounds that are useful for regulating the expression of apolipoprotein AI (ApoA-I) and their use for the treatment and prevention of cardiovascular diseases and related disease states, such as cholesterol or lipid related disorders, such as for example, atherosclerosis.

BACKGROUND OF THE INVENTION [0002] Epidemiological data show an inverse relationship between circulating blood high density lipoprotein (HDL-C) cholesterol levels and the occurrence of clinically significant atherosclerosis. Any increase in serum HDL-C level by 1 mg / dL is associated with a 2-3% reduction in the risk of cardiovascular disease; a 1% reduction in LDL-C levels contributes to a 2% reduction in coronary heart disease risk (Gordon et al. (1997) Am. J. Med. 62, 707-714). Experimental evidence further confirms the protective effect of HDL-C against cardiovascular disease. For example, in patients with low HDL-C, administration of gemfibrozil results in a 6% increase in HDL-C levels and a corresponding 22% reduction in coronary heart disease risk (Rubins et al. (1999) N. Engl. J. Med. 341, 410 -418). Observations made in the field of genetic disorders associated with low HDL-C levels due to decreased expression of ApoA-I also indicate a relationship between an increased risk of coronary heart disease and low HDL-C levels.

[0003] HDL-C appears to exert an antiatherosclerotic effect by mediating cholesterol reverse transport in which cholesterol is taken from peripheral tissues and transported to the liver. In addition, HDL-C also has anti-inflammatory and antioxidant effects and promotes fibrinolysis. HDL-C particles protect against LDL oxidation, which is an important initial step in supporting cholesterol uptake by arterial macrophages. HDL-C exists in two main forms, one containing both apolipoprotein AI (ApoA-I) and apolipoprotein A-II (ApoA-II), and the other containing ApoA-I in the absence of ApoA-II (Schultz et al. (1993 ) Nature 365, 762-764). The cardioprotective effect of HDL-C is attributed primarily, but not exclusively, to ApoA-I.

[0004] Clinical and experimental data indicate that the production of ApoA-I is a key factor for HDL-C in circulating blood. For example, people with familial hyperalphalipoproteinemia (increased ApoA-I) appear to be protected against atherosclerosis, while people with ApoA-I deficiency (hypoalfalipoproteinemia) show an accelerated cardiovascular disease. In addition, various experimental manipulations to increase ApoA-I production are associated with reduced atherogenicity. For example, human ApoA-I is protective in transgenic animal models (Shah et al. (1998) Circulation 97, 780-785; Rubin et al. (1991) Nature 353, 265-267), and treatment with ApoA -IMilano prevents atherosclerotic lesions and leads to atherosclerotic plaque regression in patients (Nissen et al. (2003) JAMA 290, 22922300). Further lines of research show that ApoA-I plays a role in increasing reverse cholesterol transport to alleviate oxidative stress, enhancing paraoxonase activity, enhancing anticoagulant activity and increasing anti-inflammatory activity (Andersson (1997) Curr. Opin. Lipidol. 8, 225-228). In this regard, ApoA-I is an attractive target for therapeutic intervention.

[0005] Currently available therapeutic agents that increase the concentration of ApoA-I in plasma, for example, recombinant ApoA-I or ApoA-I mimic peptides, have potential disadvantages with respect to, e.g. storage stability, active product delivery, and shelf life in vivo half-life. Thus, small molecules of compounds that increase the regulation of endogenous ApoA-I production, such as, for example, regulators that increase ApoA-I expression, would be very attractive as new therapeutic agents for cardiovascular disease. Such small molecule compounds are described in patent WO 2006/045038.

[0006] The compounds of the present invention represent a major advance over the compounds disclosed in patent WO 2006/045096. In particular, the compounds of the present invention are more than an order of magnitude more effective than the most active compounds described in this publication, such as 2- (4-hydroxy-phenyl) -pyran [2,3-b] pyridin-4-one.

<img file="PL2118074T3_D0001.tif" />

2- (4-hydroxy-phenyl) pyrano [2,3-b] pyridin-4-one

SUMMARY [0007] The present invention relates to non-naturally occurring compounds that are useful for regulating expression of apolipoprotein AI (ApoA-I) and their use for the treatment and prevention of cardiovascular disease and related disease states, such as cholesterol and lipid related disorders, such as , for example, atherosclerosis.

[0008] The invention includes a compound of formula II for use in increasing the expression of ApoA-I in mammals:

<img file="PL2118074T3_D0002.tif" />

wherein:

X is N;

R1 and R3 each independently are selected from alkoxy and hydrogen;

R2 is selected from alkoxy, alkyl and hydrogen;

R6 and R8 each independently are selected from alkyl, alkoxy, chloride and hydrogen;

R4 and R5 are hydrogen;

R7 is selected from amino, hydroxy, alkoxy and alkyl substituted with heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are joined together to form a heterocyclyl;

each W is independently selected from C and N; p is 1, except that when W is N, then p is 0;

wherein the "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" groups may be substituted or interrupted or branched by at least one group selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N;

with the proviso that if R2 is selected from an alkoxy group or a hydrogen atom, then at least one of R1 and R3 is an alkoxy group;

with the proviso that if R7 is selected from hydroxy or alkoxy, then at least one of R6 and R8, each independently, is selected from alkyl, alkoxy and chloride;

with the proviso that if in the case of W- (R7) p, W is N, p is 0, then at least one of R6 and R8 is chloride; and its pharmaceutically acceptable salts and hydrates.

[0009] In some embodiments of the invention, R7 is an amino group or an alkoxy group selected from the group represented by formula III:

<img file="PL2118074T3_D0003.tif" />

Formula III in which:

A is selected from O and N; n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2 -, - C (O) O- wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen; and

R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1C6) alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

[0010] In another embodiment, if A is O and B is C (O) NH-, then R20 is not unsaturated cycloalkyl.

[0011] The invention also includes a compound of formula II:

<img file="PL2118074T3_D0004.tif" />

wherein:

X is N;

R1 and R3 each independently are selected from alkoxy and hydrogen;

R2 is selected from alkoxy, alkyl and hydrogen;

R6 and R8 each independently are selected from alkyl, alkoxy, chloride and hydrogen;

R4 and R5 are hydrogen;

R7 is selected from amino, hydroxy, alkoxy and alkyl substituted with heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are joined together to form a heterocyclyl;

each W is independently selected from C and N; p is 1, except that when W is N, then p is 0;

with the proviso that if R2 is selected from an alkoxy group or a hydrogen atom, then at least one of R1 and R3 is an alkoxy group;

with the proviso that if R7 is selected from hydroxy or alkoxy, then at least one of R6 and R8, each independently, is selected from alkyl, alkoxy and chloride;

with the proviso that if in the case of W- (R7) p, W is N, p is 0, then at least one of R6 and R8 is chloride; and its pharmaceutically acceptable salts and hydrates.

[0012] In some embodiments, the compounds and compositions of the invention are useful for preventing or treating diseases that are favorably affected by elevated levels of ApoA-I or HDL, and diseases characterized by reduced levels of ApoA-I and / or HDL-C, abnormal lipid parameters or lipid parameters indicating high cholesterol. The compounds and compositions of the invention can be used to increase the expression of ApoA-I. Increased expression of ApoA-I may refer to, but not limited to, transcriptional modulation of the expression of the ApoA-I gene, which affects the level of ApoA-I protein produced (synthesized and secreted). An increase in ApoA-1 concentration may lead to an increase in HDL-C levels and / or an increase in the functionality of HDL-C particles. Thus, the compounds and compositions of the invention may additionally be used to reduce cholesterol. Accordingly, the methods, compounds and compositions of the invention can be used to treat and prevent cardiovascular disease and related disease states, in particular cholesterol or lipid related disorders such as, for example, atherosclerosis.

BRIEF DESCRIPTION OF THE DRAWINGS [0013] Figure 1 shows the plasma concentration of ApoA-I in hApoA-I transgenic mice receiving 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 7) (at 10, 30 and 60 mg / kg body weight) twice daily for 7 days by oral gavage.

Figure 2 shows plasma HDL cholesterol concentration in hApoA-I transgenic mice receiving 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxy quinazolin-4 (3H) -one (Example 7 ) (at 10 and 30 mg / kg body weight) twice daily for 7 days by oral gavage.

Figure 3 shows the plasma concentration of ApoA-I in wild-type C57BL / 6 mice receiving 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 7) (at a dose of 10, 30 and 60 mg / kg body weight) twice a day for 3 days by means of intraperitoneal administration.

Figure 4 shows plasma HDL cholesterol concentration in wild-type C57 / BI mice receiving 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) 5,7-dimethoxy quinazolin-4 (3H) -one ( Example 7) (at a dose of 10, 30 and 60 mg / kg body weight) twice a day for 3 days by oral gavage.

[0017] Figure 5 shows the ApoA-I plasma concentration and ApoA-I concentration at the mRNA level in tissues in hApoA-I transgenic mice receiving 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazoline -4 (3H) -one (Example 7) (at a dose of 30 mg / kg body weight) twice daily for 7 days by oral gavage.

DETAILED DESCRIPTION

Definitions [0018] The term "aldehyde" or "formyl" as used herein refers to -CHO.

[0019] The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched chain 2-22, 2-8 or 2-6 carbon atoms referred to herein as the (C2-C22) alkenyl, (C2-C8) alkenyl and (C2-C6) alkenyl group, respectively. Exemplary alkenyl groups include in particular vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) pentenyl, etc.

[0020] The term "alkoxy" as used herein, refers to an alkyl group attached to an oxygen atom (-O-alkyl-). "Alkoxy" groups also include an alkenyl group attached to an oxygen atom ("alkenyloxy") or an alkynyl group attached to an oxygen atom ("alkynyloxy"). Exemplary alkoxy groups include, in particular, groups containing an alkyl, alkenyl or alkynyl group having 1-22, 1-8 or 1-6 carbon atoms as referred to herein as a (C1-C22) alkoxy, (C1-C8) alkoxy group and (C1C6) alkoxy, respectively. Exemplary alkoxy groups include, in particular, methoxy, ethoxy, etc.

[0021] The term "alkyl" as used herein, refers to a straight or branched chain saturated hydrocarbon such as a straight or branched group with 1-22, 1-8 or 1-6 carbon atoms as referred to herein (C1-C22) alkyl, (C1-C8) alkyl and (C1-C6) alkyl, respectively. Exemplary alkyl groups include, in particular, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3- butyl, 2,2-dimethyl-112 propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2pentyl, 3-methyl-2-pentyl, 4 -methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl , octyl, etc.

[0022] The term "alkynyl" as used herein, refers to a straight or branched unsaturated hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched chain 2-22, 2-8 or 2-6 group carbon atoms referred to herein as a (C2-C22) alkynyl, (C2-C8) alkynyl and (C2-C6) alkynyl group, respectively. Exemplary alkynyl groups include, in particular, ethynyl, propynyl, butynyl, pentynyl, hexinyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl and 4-butyl-2-hexynyl, etc.

[0023] As used herein, the term "amide" refers to the form NRaC (O) (Rb) - or -C (O) NRbRc, wherein Ra, Rb and Rc, each independently, is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. The amide can be attached to another group with carbon, nitrogen, Rb or Rc. The amide may also be in a cyclic form, for example Rb and Rc may be joined to form a ring

A 3-12 member, such as a 3-10 member ring or a 5-6 member ring. The term "amide" includes groups such as sulfonamide, urea, ureide, carbamate, carbamic acid and their cyclic forms. The term "amide" also includes an amide group attached to a carboxyl group, e.g., -amido-COOH or salts such as -amido-COONa, etc., an amino group attached to the carboxyl group, e.g., -amino-COOH or salts , such as -amino-COON, etc.

[0024] The term "amine" or "amino" as used herein refers to the -NRdRe or -N (Rd) Re- form in which Rd and Re, each independently, is selected from alkyl, alkenyl, alkynyl, aryl , arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. The amino group can be attached to the parent molecular group via a nitrogen atom. The amino group may also have a cyclic form, for example two of Rd and Re may be attached to each other or with N to form a 312-membered ring, e.g., a morpholinyl or piperidinyl group. The term "amino"

also includes the quaternary ammonium salt of any amino group.

Exemplary amino groups include alkylamino groups wherein at least one of Rd or Re is an alkyl group.

[0025] The term "aryl" as used herein refers to a mono-, or other multicarbocyclic aromatic ring system. The aryl group may be optionally linked to one or more rings selected from aryl, cycloalkyl and heterocyclyl. The aryl groups of the present invention may be substituted with groups selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Exemplary aryl groups include in particular phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl as well as benzofused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include in particular a monocyclic aromatic ring system in which the ring consists of 6 carbon atoms, referred to herein as the "(C6) aryl group".

[0026] The term "arylalkyl" as used herein, refers to an alkyl group having at least one aryl substituent, e.g., -aryl-alkyl. Exemplary arylalkyl groups include, in particular, arylalkyls having a monocyclic aromatic ring system in which the ring consists of 6 carbon atoms, referred to herein as the "(C5) arylalkyl group."

[0027] The term "aryloxy" as used herein refers to an aryl group attached to an oxygen atom. Exemplary aryloxy groups include, in particular, aryloxy groups having a monocyclic aromatic ring system in which the ring consists of 6 carbon atoms, referred to herein as the "(C6) aryloxy group."

[0028] The term "arylthio" as used herein refers to an aryl group attached to a sulfur atom. Exemplary arylthio groups include, in particular, arylthio groups having a monocyclic aromatic ring system in which the ring consists of 6 carbon atoms, referred to herein as the "(C6) arylthio group."

[0029] The term "arylsulfonyl" as used herein, refers to an aryl group attached to a sulfonyl group, e.g., -S (O) 2-aryl-. Exemplary arylsulfonyl groups include, in particular, arylsulfonyl groups having a monocyclic aromatic ring system in which the ring consists of 6 carbon atoms, referred to herein as the "(C6) arylsulfonyl group."

[0030] The term "benzyl" as used herein refers to the CH2-phenyl group.

[0031] The term "bicyclic aryl" as used herein refers to an aryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic aryl groups include, in particular, naphthyl or partially reduced forms such as di-, tetra- or hexahydronaphthyl.

[0032] The term "bicyclic heteroaryl" as used herein refers to a heteroaryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic heteroaryl groups include in particular 5.6- or

6,6-fused systems in which one or both rings contain heteroatoms. The term "bicyclic heteroaryl" also includes reduced or partially reduced forms of a fused aromatic system in which one or both rings contain heteroatoms. The ring system may contain up to three heteroatoms independently selected from oxygen, nitrogen or sulfur. The bicyclic system may be optionally substituted with one or more groups selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Exemplary bicyclic heteroaryl groups include, in particular, quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl and benzofuranyl.

[0033] The term "carbamate" as used herein refers to the -RgOC (O) N (Rh) -, -RgOC (O) N (Rh) Rr or -OC (O) NRhRi form in which Rg, Rh and R1 each independently is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. Exemplary carbamates include, in particular, arylcarbamates or heteroarylcarbamates, e.g., wherein at least one of Rg, Rh and Ri is independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine and pyrazine.

[0034] The term "carbonyl" as used herein, refers to the group -C (O) -.

[0035] The term "carboxy" as used herein refers to the group -COOH or its corresponding carboxylate salts, e.g. -COONa, etc. The term "carboxy" also includes the term "carboxycarbonyl," e.g., a carboxy group attached to a carbonyl group, e.g. -C (O) -COOH or salts such as -C (O) -COONa, etc.

[0036] The term "cyano" as used herein, refers to -CN.

[0037] The term "cycloalkoxy" as used herein, refers to a cycloalkyl group attached to an oxygen atom.

[0038] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group of 3-12 carbon atoms or 3-8 carbon atoms referred to herein as the "group (C3- C8) cycloalkyl, "derived from cycloalkane. Exemplary cycloalkyl groups include, in particular, cyclohexanes, cyclohexenes, cyclopentanes and cyclopentenes. Cycloalkyl groups may be substituted with groups selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Cycloalkyl groups can be fused with other saturated or unsaturated, aryl or heterocyclyl cycloalkyl groups.

[0039] The term "dicarboxylic acid" as used herein refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and their salts. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. The dicarboxylic acids may be substituted with groups selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxy, nitro, hydroxy sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Dicarboxylic acids include in particular succinic acid, glutaric acid, adipic acid, corkic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+) / (-) malic acid , (+) / (-) tartaric acid, isophthalic acid and terephthalic acid. The dicarboxylic acids further include their derivatives in the form of carboxylic acids, such as anhydrides, imides, hydrazides, etc., for example, succinic anhydride, succinic imide, etc.

[0040] The term "ester" refers to the structure -C (O) O-, -C (O) O-Rj, -RkC (O) ORj or -RkC (O) O-, wherein O is not bonded to hydrogen, and Rj and Rk may be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, halogenoalkyl, heteroaryl, heterocyclyl. Rk may be hydrogen, but Rj may not be hydrogen. The ester may be cyclic, for example carbon and Rj, oxygen and Rk, or Rj and Rk may be joined to form a 3-12 membered ring. Exemplary esters include, in particular, alkyl esters in which at least one of Rj or Rk is an alkyl group such as -OC (O) alkyl, -C (O) -O-alkyl-, -alkyl-C (O) -O-alkyl-, etc. Examples of esters are also aryl or heteroaryl esters, e.g. such that at least one of Rj and Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine, such as nicotinate ester. Exemplary esters also include reversible esters having the structure RkC (O) O-, where the oxygen atom is attached to the parent molecule. Examples of reversible esters include succinate, D-arginate, L-arginate, L-lysine and D-lysine. Esters also include carboxylic acid anhydrides and acid halides.

[0041] The term "ether" refers to the structure -R10-Rm-, wherein R1 and Rm may be independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl or ether. The ether can be attached to the parent molecular group using R1 and Rm. Examples of ethers include, in particular, alkoxyalkyl and alkoxyaryl. The ethers also include polyethers, e.g. wherein one or both R1 and Rm are the ethers.

[0042] The terms "halogen" or "halogen" or "Hal" as used herein refer to F, CI, Br or I.

[0043] The term "haloalkyl" as used herein, refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyl" groups also include alkenyl or alkynyl groups substituted with one or more halogen atoms.

[0044] The term "heteroaryl" as used herein refers to a mono-, bi- or multicarbocyclic aromatic ring system containing one or more heteroatoms, for example from 1 to 3 heteroatoms such as nitrogen, oxygen and sulfur. Heteroaryl groups may be substituted by one or more substituents selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Heteroaryl groups can also be fused to non-aromatic rings. Selected examples of heteroaryl groups include, in particular, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) and (1,2,4) -triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl , isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include in particular a monocyclic aromatic ring in which the ring consists of 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as the "(C2-C5) heteroaryl group".

[0045] The terms "heterocycle," "heterocyclyl" or "heterocyclic" as used herein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected among nitrogen, oxygen and sulfur. Heterocyclic groups can be aromatic (heteroaryl groups) or non-aromatic. Heterocyclic groups may be substituted by one or more substituents selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups. Heterocyclic groups also include bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings are fused to one or two rings independently selected from cycloalkyl, aryl and heterocycles. Exemplary heterocyclic groups include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzoxyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolinyl, imidazolinyl zotiazolil, isoxazolidinyl , isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrolinyl, pyrrolyl, quinolinyl, quinoxalyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, triethiolyl, thiazolyl, thiazilyl, thiazolyl, thiazolyl

[0046] As used herein, the terms "hydroxy" or "hydroxy" refer to -OH.

[0047] The term "hydroxyalkyl" as used herein, refers to a hydroxyl group attached to an alkyl group.

[0048] The term "hydroxyaryl" as used herein, refers to a hydroxyl group attached to an aryl group.

[0049] The term "ketone" as used herein refers to the structure -C (O) -Rn (such as acetyl, -C (O) CH3) or -Rn-C (O) -RO-. The ketone can be attached to another group with Rn or Ro substituents. Rn or Ro may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rn or Ro may be joined to form a 3-12 membered ring.

[0050] As used herein, the term "monoester" refers to a dicarboxylic acid analog in which one carboxylic acid is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or carboxylic acid salt. Examples of monoesters include, in particular, monoesters of succinic acid, glutaric acid, adipic acid, corkic acid, sebacic acid, azelaic acid, oxalic acid and maleic acid.

[0051] The term "nitro" as used herein, refers to -NO2. [0052] The term "perfluoroalkoxy" as used herein, refers to an alkoxy group in which all hydrogen atoms have been replaced by fluorine atoms.

[0053] The term "perfluoroalkyl" as used herein, refers to an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms. Exemplary perfluoroalkyl groups include, in particular, C1-5 perfluoroalkyl, such as trifluoromethyl, etc.

[0054] The term "perfluorocycloalkyl" as used herein refers to a cycloalkyl group in which all hydrogen atoms have been replaced by fluorine atoms.

[0055] The term "phenyl" as used herein refers to a 6 membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. Phenyl may be substituted by one or more substituents selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone groups.

[0056] The term "phosphate" as used herein refers to the structure -OP (O) O2-, -RxP (O) O2-, -OP (O) O2Ry- or -RxOP (O) O2Ry-, in which Rx and Ry may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, hydrogen.

[0057] As used herein, the term "sulfide" refers to the structure -RzS-, wherein Rz may be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl. The sulphide can be cyclic to form a 3-12 membered ring. The term "alkylsulfide" as used herein, refers to an alkyl group attached to a sulfur atom.

[0058] The term "sulfinyl" as used herein refers to the structure -S (O) O-, -RpS (O) O-, -RpS (O) ORq- or -S (O) ORq-, where Rp and Rq may be alkyl, alkenyl, aryl, aralkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxy. Exemplary sulfinyl groups include, in particular, alkylsulfinyl groups in which at least one of Rp or Rq is alkyl, alkenyl or alkynyl.

[0059] The term "sulfonamide" as used herein refers to the structure - (Rr) -NS (O) 2-Rs- or -Rt (Rr) -NS (O) 2-Rs, where Rt, Rr and Rs may be, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (e.g., where Rs is alkyl), arylsulfonamides (e.g., where Rs is aryl), cycloalkyl sulfonamides (e.g., where Rs is cycloalkyl), and heterocyclic sulfonamides (e.g. such where Rs is heterocyclyl), etc.

[0060] The term "sulfonate" as used herein refers to OSO3-. The sulfonate includes salts such as -OSO3Na, -OSO3K, etc., and OSO3H acid.

[0061] The term "sulfonic acid" refers to -SO3H- and its corresponding salts, e.g. -SO₃K-, -SO₃On-.

[0062] The term "sulfonyl" as used herein refers to the structure of RuSO2-, wherein Ru may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl, e.g., alkylsulfonyl. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group. "Alkylsulfonyl" groups may optionally contain alkenyl or alkynyl groups.

[0063] The term "thioketone" refers to the structure -Rv-C (S) -Rw-. The ketone can be attached to another group with Rv or Rw substituents. Rv or Rw may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rv or Rw may be joined to form a 3-12 membered ring.

[0064] "Alkyl," "alkenyl," "alkynyl", "alkoxy", "amino" and "amide" groups may be substituted or interrupted or branched by at least one group selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N. Substituents can be branched to form a substituted or unsubstituted heterocycle or cycloalkyl. [0065] The term "suitable substituent," as used herein, refers to a group that does not impair the synthetic or pharmaceutical utility of the compounds of this invention or the intermediates useful in their preparation. Examples of suitable substituents include, in particular: C1-22, C1-8 and C1-6 alkyl, alkenyl or alkynyl; C1-6 aryl,

C2-5 heteroaryl; C3-7 cycloalkyl; C1-22, C1-8 and C1-6 alkoxy; C6 aryloxy; CN; OH;

oxo; halogen, carboxy; amino groups such as -NH (C_1-22, C._1-8 or C._1-6 alkyl), -N (C1-22, C1-8 and C1-6 alkyl) 2, -NH ((C6) aryl) or -N ((C6) aryl) 2; formyl; ketones such as -CO (C1-22, C1-8 and C1-6 alkyl), -CO ((C6 aryl); esters such as -CO2 (C1-22, C1-8 and C16 alkyl) and -CO2 (C6 aryl) A person skilled in the art can easily choose the appropriate substituent based on the stability and the pharmacological and synthetic activity of the compound of the invention.

[0066] The term "pharmaceutically acceptable carrier" as used herein refers to all solvents, dispersion carriers, coatings, isotonic and absorption delaying agents, and similar agents that are suitable for pharmaceutical administration. The use of such carriers and agents with respect to pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary and additional therapeutically improved functions.

[0067] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein, prepared together with one or more pharmaceutically acceptable carriers.

[0068] The term "pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds of the present invention that are, within reasonable medical judgment, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reaction, commensurate with a reasonable benefit-risk balance, and effective for their intended use, as well as zwitterions (there, where possible) of compounds of the present invention. Discussion is presented in Higuchi et al., "Pro-drugs as new administration systems," ACS Symposium Series, volume 14, and Roche, EB, ed. Bioreversible Carriers in Drug Development, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0069] The term "pharmaceutically acceptable salt / pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. The compounds contained in the compositions of the present invention, which are basic in nature, are capable of forming a wide range of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, in particular sulfate, citrate, malate, acetate, oxalate, chloride, bromide salts , iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, gluconate, saccharate, formate, benzoate, glutamate, mesylate, mesylate, mesylate, methylene-bis- (2-hydroxy-3naftoesan)). Compounds contained in compositions of the present invention that contain an amino residue may form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. The compounds contained in the compositions of the present invention that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular, calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

[0070] The compounds of the present invention may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" as used herein includes all geometric isomers, enantiomers or diastereomers. These compounds may be denoted by the symbols "R" or "S", depending on the configuration of the substituents around the stereogenic carbon atom. The present invention includes the various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated as "(±)" in the nomenclature, but one of ordinary skill in the art will recognize that the structure may implicitly point to a center of chirality.

[0071] Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparing racemic mixtures followed by separation methods well known to those skilled in the art. These separation methods are illustrated, for example, by (1) attaching a mixture of enantiomers to a chiral excipient, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the excipient, (2) salt formation using an optically active resolving agent, or (3) ) direct separation of a mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be separated into their stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

[0072] Geometric isomers may also exist in the compounds of the present invention. The present invention includes various geometric isomers and mixtures thereof resulting from the arrangement of substituents around the carbon-carbon double bond or the arrangement of substituents around the carbocyclic ring. Substituents arranged around a carbon-carbon double bond are referred to as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures representing double bonds include both E isomers and Z isomers.

[0073] Substituents arranged around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans", where "cis" includes substituents arranged on the same side of the double bond and "trans" includes substituents arranged on opposite sides of the double bond. The position of the substituents around the carbocyclic ring is designated "cis" or "trans". The term "cis" means substituents on the same side of the ring plane, and the term "trans" means substituents on opposite sides of the ring plane. Mixtures of compounds in which the substituents are arranged on both the same or opposite sides of the ring plane are designated "cis / trans".

Embodiments of the Invention [0074] The following is a list of specific embodiments that are covered by the invention:

1. A compound of formula II for use in increasing the expression of ApoA-I in mammals:

<img file="PL2118074T3_D0005.tif" />

wherein:

X is N;

R1 and R3 each independently are selected from alkoxy and hydrogen;

R2 is selected from alkoxy, alkyl and hydrogen;

R6 and R8 each independently are selected from alkyl, alkoxy, chloride and hydrogen;

R4 and R5 are hydrogen;

R7 is selected from amino, hydroxy, alkoxy and alkyl substituted with heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are joined together to form a heterocyclyl;

each W is independently selected from C and N; p is 1, except that when W is N, then p is 0;

wherein the "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and amide "may be substituted or interrupted or branched by at least one group selected from the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic, cyano, cycloalkyl, ester, ether, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phosphate, ketone sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N;

with the proviso that if R2 is selected from an alkoxy group or a hydrogen atom, then at least one of R1 and R3 is an alkoxy group;

with the proviso that if R7 is selected from hydroxy or alkoxy, then at least one of R6 and R8, each independently, is selected from alkyl, alkoxy and chloride;

with the proviso that if in the case of W- (R7) p, W is N, p is 0, then at least one of R6 and R8 is chloride;

and its pharmaceutically acceptable salts and hydrates.

2. The compound for use according to embodiment 1, wherein at least one of R6 and R8 is selected from alkyl, alkoxy and chloride.

3. The compound for use according to embodiment 1, wherein R6 and R8 are each hydrogen and W- (R7) p is C- (R7) 1.

4. The compound for use according to Embodiment 1 or Embodiment 2 wherein none of R6 and R8 are hydrogen.

5. The compound for use according to any one of embodiments 1, 2 and

4 in which

R1 and R3 are alkoxy;

R6 and R8 are alkyl; and

R7 is an alkoxy group substituted with a hydroxyl group.

6. The compound for use according to embodiment 1, wherein the substituent

R7 is selected from hydroxyl and alkoxy.

7. The compound for use according to embodiment 1, wherein the compound of formula II is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 7);

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 4);

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (Example 7);

3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyquinazolin-1 (2H) -one (Example 8);

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 9);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 10);

2- (4-bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (Example 11);

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one (Example 12);

2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 13);

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrido [2,3550 d] pyrimidin-4 (3H) -one (Example 14);

2- (2-chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 15);

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one (Example 16);

555 2- (4-amino-3,5-dimethyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 17);

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (Example 18);

2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

560 (Example 18); and

4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 20).

8. The compound for use according to embodiment 1, wherein the 565 R7 substituent is an amino group or an alkoxy group selected from the group represented by formula III:

<img file="PL2118074T3_D0006.tif" />

570 wherein:

A is selected from O and N; n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2 -, - C (O) O- wherein each Rh is selected from the alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen atom group; and

R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1C6) alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

In another embodiment, if A is O and B is -C (O) NH-, then R20 is not unsaturated cycloalkyl.

9. The compound for use according to embodiment 8, wherein the compound of formula II is selected from:

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (Example 19);

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methalphalamide (Example 21);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (Example 22);

4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 23).

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide (Example 24);

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl propylcarbamate (Example 25);

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate (Example 26);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide (Example 27);

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate (Example 28);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 29);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide (Example 30);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide (Example 31);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide (Example 32);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide (Example 33);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide (Example 34);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea (Example 35);

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea (Example 36);

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea (Example 37);

3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethyl urea (Example 38);

10. The compound for use according to embodiment 1, wherein the therapeutically effective amount of the compound of formula II is to be administered in combination with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

11. The compound for use according to embodiment 1, further serving to treat or prevent cardiovascular disorders and cholesterol or lipid related disorders.

12. Compound of formula II:

<img file="PL2118074T3_D0007.tif" />

wherein:

X is N;

R1 and R3 each independently are selected from alkoxy and hydrogen;

R2 is selected from alkoxy, alkyl and hydrogen;

R6 and R8 each independently are selected from alkyl, alkoxy, chloride and hydrogen;

R4 and R⁵ are hydrogen;

R7 is selected from amino, hydroxy, alkoxy and alkyl substituted with heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are joined together to form a heterocyclyl; each W is independently selected from C and N;

p is 1, except that when W is N, then p is 0; with the proviso that if R2 is selected from an alkoxy group or a hydrogen atom, then at least one of R1 and R3 is an alkoxy group;

with the proviso that if R7 is selected from hydroxy or alkoxy, then at least one of R6 and R8, each independently, is selected from alkyl, alkoxy and chloride;

with the proviso that if in the case of W- (R7) p, W is N, p is 0, then at least one of R6 and R8 is chloride;

and its pharmaceutically acceptable salts and hydrates.

13. The compound of embodiment 12, wherein the compound is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 7).

14. The compound of embodiment 12, wherein the compound of formula II is selected from the following:

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example

4);

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 7);

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 9);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 10);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (Example 11);

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one (Example 12);

2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 13);

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrido [2,3d] pyrimidin-4 (3H) -one (Example 14);

2- (2-chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example

15);

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one (Example

16);

2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example

17);

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (Example 18);

2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (Example 18); and

4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 20).

15. The compound of embodiment 12, wherein R7 is an amino group or an alkoxy group selected from the group represented by formula III:

<img file="PL2118074T3_D0008.tif" />

Formula III in which:

A is selected from O and N; n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2 -, - C (O) O- wherein each Rh is selected from the alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen atom group; and

R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

In another embodiment, if A is O and B is -C (O) NH-, then R20 is not unsaturated cycloalkyl.

16. The compound of embodiment 15, wherein the compound of formula II is selected from the following:

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) 4-methoxybenzenesulfonamide (Example 19);

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (Example 21);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (Example 22);

4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 23);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide (Example 24);

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl propylcarbamate (Example 25); 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate (Example 26);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide (Example 27);

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate (Example 28);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (Example 29);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide (Example 30);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) 4-methoxybenzamide (Example 31);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide (Example 32);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide (Example 33);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide (Example 34);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,8-dimethylphenoxy) ethyl) -3-methylurea (Example 35);

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea (Example 36);

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea (Example 37); and

3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethyl urea (Example 38);

17. A pharmaceutical composition comprising the compound of embodiment 12 and a pharmaceutically acceptable carrier.

18. The compound of embodiment 12 for use in the treatment of cardiovascular disorders and associated with cholesterol or lipids.

19. The compound of embodiment 12 for use in increasing the expression of ApoA-1 in mammals.

Pharmaceutical compositions and uses in treatment [0075] The present invention also provides pharmaceutical compositions containing the compounds disclosed herein prepared together with one or more pharmaceutically acceptable carriers. These preparations include those suitable for oral, rectal, topical, buccal and parenteral administration (e.g. subcutaneous, intramuscular, intradermal or intravenous), although the most appropriate route of administration in each case will depend on the degree and severity of the condition being treated and the type of specific compound being used.

[0076] Formulations suitable for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each unit containing a predetermined amount of the compound in powder or granular form; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of oil-in-water or water-in-oil emulsions. As already mentioned, such preparations can be prepared by any suitable pharmaceutical method, which includes the step of bringing into association the active ingredient and the carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense that it will be compatible with the other ingredients of the preparation and will not be harmful to the recipient. The carrier may be in solid or liquid form, or both, and may be prepared together with the compound as a unit dose formulation, for example, in the form of a tablet, which may contain from about 0.05% to about 95% by weight of the active ingredient. Other pharmacologically active substances may also be present, including other compounds. The formulations of the present invention can be prepared by any of the well-known pharmaceutical techniques consisting essentially of mixing ingredients.

[0077] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical forms of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. Liquid compositions for pharmaceutical administration may be prepared, e.g. by dissolving, dispersing, etc., the active compound as described herein and optional pharmaceutical adjuvants in an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like to form the solution or suspension method. In general, suitable formulations can be prepared by uniformly and intimately mixing the active compound with a liquid or finely divided solid carrier, or in both, and then, if necessary, by shaping the product. For example, a tablet may be made by compressing or molding the powder or granulate of the compound, optionally with one or more accessory ingredients. Compressed tablets can be made by compressing, in a suitable machine, a loose compound, such as a powder or granules, optionally mixed with a binder, glidant, inert diluent and / or surfactant (s) / dispersant (s) . Molded tablets can be made by molding, in a suitable machine, a powdered compound moistened with an inert liquid diluent.

[0078] Formulations suitable for buccal (sublingual) administration include lozenges containing the compound in an flavored base, usually sucrose and acacia or tragacanth, and pastilles containing the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0079] Formulations of the present invention suitable for parenteral administration include sterile aqueous preparations of the compounds that are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although they may also be administered by subcutaneous, intramuscular or intradermal injection. Such preparations can be conveniently prepared by mixing the compound with water and giving the resulting solution a sterile and isotonic character with blood.

Injectable compositions of the present invention may contain from about 0.1 to about 5% by weight of the active compound.

[0080] Formulations suitable for rectal administration are in the form of suppositories with a unit dose. They can be prepared by mixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then by shaping the resulting mixture.

[0081] Formulations suitable for topical application to the skin may be in the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Carriers and excipients that may be used include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of them. The active compound is generally present at a concentration of from about 0.1% to about 15% by weight of the total composition, for example, from about 0.5 to about 2%.

[0082] The amount of active compound administered may depend on the patient being treated, the weight of the patient, the method of administration and assessment of the treating physician. For example, the dosage regimen may include once or twice daily administration of the encapsulated compound at a fixed dose of from about 1 µg to about 1000 mg. In another embodiment, intermittent dosing of the encapsulated compound may be used, e.g., on a monthly or annual basis. Encapsulation facilitates access to the site of action and allows simultaneous administration of active ingredients, theoretically producing a synergistic effect. According to standard dosage regimens, it will be easy for the physician to determine optimal doses and will be able to easily modify the administration to achieve such doses.

[0083] A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of that compound. However, doses may vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. In one embodiment, the therapeutically effective amount of the compound disclosed is sufficient to determine the maximum plasma concentration. Initial doses determined, for example, in accordance with animal studies, and dose scaling for administration to humans, are determined

870 in accordance with accepted practice in the field.

[0084] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals, e.g. by determining LD50 (lethal dose for 50% of the population) and ED50 (therapeutically effective dose for 50%

875 population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit high therapeutic indices are preferred.

[0085] Data obtained from cell culture assays or animal studies can be used to determine the dosage range for use in human

880 people. Therapeutically effective doses obtained in one animal model can be converted for use in other animals, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50 (4): 219-244 ( 1966) and Table in relation to Equivalent Dose Factors

885 s).

Table 1

<td>Down:</td><td>Mouse</td><td>Rat</td><td>Monkey</td><td>Dog</td><td>Man</td>

<td>FROM:</td><td>(20 g)</td><td>(150 g)</td><td>^{(3.5 k}g)</td><td>(8 kg)</td><td>(60 kg)</td>

<td>Mouse</td><td> 1</td><td> 1/2</td><td> 1/4</td><td> 1/6</td><td> 1/12</td>

<td>Rat</td><td> 2</td><td> 1</td><td> 1/2</td><td> 1/4</td><td> 1/7</td>

<td>Monkey</td><td> 4</td><td> 2</td><td> 1</td><td> 3/5</td><td> 1/3</td>

<td>Dog</td><td> 6</td><td> 4</td><td> 3/5</td><td> 1</td><td> 1/2</td>

<td>Man</td><td> 12</td><td> 7</td><td> 3</td><td> 2</td><td> 1</td>

[0086] The dosage of such compounds is preferably dependent on the concentration range of 890 in the circulating blood, which includes ED50 with little or no toxicity.

Dosage may vary within this range depending on the dosage form employed and the route of administration used. Generally, a therapeutically effective amount may vary depending on the patient's age, sex and condition, as well as the severity of the patient's condition. The dose can be determined by the doctor and adjusted, if necessary, to the observed effects of treatment.

[0087] In one embodiment, the compound of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, is to be administered in combination with another therapeutic agent. The other therapeutic agent may add value or synergistic to the administration of the compound of the present invention alone. The therapeutic agent may be, for example, a statin; PPAR receptor agonist, e.g. thiazolidinedione or fibrate; niacin, an RVK, FXR or LXR receptor agonist; bile acid reuptake inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor; ion exchange resin; antioxidant; cholesterol acyltransferase inhibitor

AcyloCoA (ACAT inhibitor); tyrofostyna; a drug based on a sulfonylurea; biguanide; alpha-glucosidase inhibitor; apolipoprotein E regulator; HMG-CoA reductase inhibitor, microsomal triglyceride transfer protein; LDL lowering drug; HDL-raising drug; HDL amplifier; regulator of the apolipoprotein A-IV gene and / or the apolipoprotein gene; or any drug for the treatment of the cardiovascular system.

[0088] In one embodiment, a therapeutically effective amount of a compound disclosed is used to treat or prevent cardiovascular disease and cholesterol or lipid related disorders in a mammal (e.g., human). The compound of the present invention may be administered as a pharmaceutically acceptable composition comprising the disclosed compound and a pharmaceutically acceptable carrier.

[0089] The term "cardiovascular disease" as used herein refers to diseases and disorders of the heart and circulatory system. Exemplary cardiovascular diseases, including cholesterol and lipid related disorders, include in particular acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular diseases, ischemic stroke, congestive heart failure, congenital heart disease, coronary artery disease, coronary artery disease, coronary artery plaque stabilization, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial associated hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridaemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemic disease, ischemic disease, ischemic ischemia, ischemic ischemia, ischemic disease, ischemia, ischemia peripheral vessels, reperfusion injury, restenosis, renal atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attacks and lipoprotein disorders associated with Alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, Parkinson's disease and inflammatory diseases.

[0090] One embodiment provides compounds for use in altering a patient's lipid metabolism, e.g., by increasing the ratio of HDL to LDL or ApoA-I to ApoB in the patient's blood, wherein the composition of the present invention is to be administered in an amount sufficient to changes in lipid metabolism.

[0091] One embodiment provides compositions for use in raising levels of ApoA-I-associated molecules such as HDL in mammalian blood, wherein a composition comprising the disclosed compound or disclosed composition in an amount sufficient to raise the level of related proteins is to be administered. with ApoA-I and HDL in mammals.

[0092] In one embodiment, the terms "treating" or "for treating" refer to ameliorating a disease or disorder or at least one perceptible symptom of said disease or disorder. In another embodiment, the terms "treatment" or "for treatment" refer to the amelioration of at least one measurable physical parameter not necessarily perceived by the patient. And in yet another embodiment, the terms "treating" or "for treating" refer to inhibiting the development of a disease or disorder, in a physical manner, e.g., stabilization of a perceptible symptom, in a physiological manner, e.g., stabilization of a physical parameter, or both. . In another embodiment, the terms "treating" or "for treating" refer to delaying the onset of a disease or disorder.

For example, treatment of a cholesterol-related disorder may include lowering blood cholesterol.

[0093] One embodiment relates to a compound for administration to a patient, such as a human, as a preventive measure against cardiovascular diseases, including cholesterol or lipid related disorders. The terms "prevention" or "for prevention" as used herein refer to reducing the risk of a given disease or disorder. An additional aspect provides a composition / compound for use in preventing the development of lesions in atherosclerosis in mammals, including the development of new atherosclerotic lesions. In another aspect, the present invention provides a composition / compound for use in regression of arteriosclerosis.

[0094] In another embodiment, the compositions of the present invention are intended to be administered as a preventive measure to a patient, such as a person with a genetic predisposition to cardiovascular disease, including cholesterol or lipid related disorders, e.g. familial hypercholesterolemia, familial associated hyperlipidemia, atherosclerosis, dyslipidemia, dyslipoproteinemia or Alzheimer's disease.

[0095] In another embodiment, the compositions of the present invention are intended to be administered as a preventive agent to a patient with a non-genetic predisposition to cardiovascular disease, including cholesterol or lipid related disorders. Examples of such non-genetic predispositions include, in particular, coronary artery bypass surgery and percutaneous intravascular coronary angioplasty, which often leads to restenosis, a faster form of atherosclerosis; diabetes in women, which often leads to polycystic ovary syndrome, and cardiovascular disease, which often leads to impotence.

[0096] Angioplasty and open heart surgery, such as coronary bypass surgery, may be necessary for the treatment of cardiovascular diseases such as atherosclerosis. Such surgical procedures involve the use of invasive surgical instruments and / or implants and are associated with a high risk of restenosis and thrombosis. Accordingly, the compounds of the present invention can be used as coatings for surgical instruments (e.g. catheters) and implants (e.g. stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used to treat cardiovascular disease.

[0097] In another embodiment, the compositions of the present invention may be used to prevent one disease or disorder and simultaneously treat another disease or disorder (e.g., prevention of polycystic ovarian syndrome during treatment of diabetes; prevention of impotence during treatment of cardiovascular disease).

[0098] Diseases and conditions associated with "diabetes mellitus" (diabetes mellitus) as defined herein relate to chronic metabolism disorders due to absolute or relative insulin deficiency, in particular, hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism , obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, skin and connective tissue disorders, foot ulcers, metabolic acidosis, arthritis, osteoporosis and glucose tolerance disorders.

PREPARATION OF COMPOUNDS [0099] Exemplary compounds of the present invention of general formula A:

<img file="PL2118074T3_D0009.tif" />

wherein:

Ra may be selected from groups including in particular the following

1020 alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ether, halogen, halogenoalkyl, heteroaryl, heterocyclyl, hydrogen and hydroxy groups; Rb may be selected from groups including in particular the following groups: alkyl and hydrogen; X may be selected from, e.g. CRc, N and NRc,

1025 wherein Rc is substituents such as alkyl, alkenyl, alkynyl and hydrogen; Y may be selected from, e.g. CO, CS and SO2-; and Z3 may be a single or double bond; they can be synthesized from readily available starting materials as exemplified in the schemes below. It should be noted that these terms are non-limiting examples.

1030

<img file="PL2118074T3_D0010.tif" />

condensation = condensation

Diagram 1

1035 [0100] Scheme 1 illustrates the fact that condensation followed by oxidation of amide 1 and aldehyde 2 can lead to the formation of quinozolinone 3. Condensation can occur under a variety of conditions, such as NaHSO3 and p-TsOH in dimethylacetamide, I2 in the presence of K2CO3 and catalytic treatment trifluoroacetic acid followed by DDQ oxidation.

<img file="PL2118074T3_D0011.tif" />

Scheme 2 [0101] Condensation of amide 4 with nitrile 5 in the presence of n-BuLi may lead to the formation of isoquinolinone 6, as shown in scheme 2.

<img file="PL2118074T3_D0012.tif" />

Scheme 3 [0102] Scheme 3 shows a method for the synthesis of benzothiazine-1,1-dioxide 9. Amide coupling of sulfonamide 7 with carboxylic acid 8 followed by treatment with n-BuLi may give 9.

EXAMPLES [0103] Abbreviations used herein denote the following compounds, reagents and substituents: acetic acid (AcOH); 2,2'-azobisisobutyronitrile (AIBN); N-bromosuccinimide (NBS); N-tert-butoxycarbonyl (Boc); t-butyldimethylsilyl (TB-DMS); m-chloroperbenzoic acid (mCPBA);

dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc); 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 1-hydroxybenzotriazole (HOBt); iodomethane (Mel); lithium hexamethyldisilazide (LHMDS); methanol 1065 (MeOH); methoxymethyl (MSM); tetrahydrofuran (THF); triethylamine (Et3N);

lithium aluminum hydride (LAH); p-toluenesulfonic acid (p-TSA); tetrabutylammonium fluoride (TBAF); N-methylmorpholine (NMM); N, N-dimethylacetamide (DMA); twice a day (BID), once a day (QD).

1070 Example 1 (Reference example) [0104]

<img file="PL2118074T3_D0013.tif" />

1075 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one To the suspension of 2-methyl-4,6-dimethoxy-benzoic acid (2.61 g, 13 , 1 mmol) in CH 2 Cl 2 (50 mL) oxalyl chloride (3.38 g, 26.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours.

1080 The solvent and excess oxalyl chloride were removed under reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine (1.24 g, 39.9 mmol) with cooling and stirred at room temperature for 4 hours. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2 to give the amide (2.27 g,

1085 82%). To a solution of the above amide (2.27 g, 10.9 mmol) in THF (50 mL), n-butyllithium (9.98 mL, 25.0 mmol, 2.5 M solution in hexane) was slowly added under a nitrogen atmosphere. cooling, keeping the temperature below 20 ° C.

The mixture was stirred for 1 hour. at 0 ° C, then cooled to -50 ° C and a solution of 4-O-TBDMS-3,5-dimethylbenzonitrile (2.97 g, 11.39 mmol) in THF (10 ml), bath was added quickly cooling was removed and the reaction mixture was stirred for 16 h. in room temperature. A saturated aqueous NH4Cl solution was added with cooling, and then the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give 3.9 g of a crude product mixture. The suspension

1095 mixtures of the crude product (3.9 g) in ethanol (20 ml) were heated with conc. HCl (2 ml) at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature and the solvent removed. The solid was dissolved in water and neutralized with NaHCO3, followed by extraction with CH2Cl2. The product was purified by chromatography to yield two

1100 products: 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-2-methylisoquinolin-1 (2H) -one (128 mg, 5%) and 3- (4-hydroxy-3,5-dimethylphenyl) - 6,8-dimethoxyisoquinolin-1 (2H) -one (340 mg, 9%). Selected data for 3- (4-hydroxy-3,5-dimethylphenyl) -8,8-dimethoxyisoquinolin-1 (2H) on: MS (ES) m / z: 326.00; MP 226-227 ° C.

1105

Example 2 (Reference example) [0106]

<img file="PL2118074T3_D0014.tif" />

- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one [0107] To a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6 , 79 mmol) in DMF (100 mL) added NaH (1.065 g, 26.63 mmol) and (2-bromoethoxy) -tert-butyldimethylsilane (1.85 g, 8.15 mmol). The reaction mixture was stirred for 10 days at room temperature under nitrogen. The reaction mixture was poured into ice water and the products were extracted with ethyl acetate. The organic layer was separated, washed with water, dried and concentrated to give a crude product which was purified by column chromatography to give 1.9 g of block forming ring B in 92% yield.

N-butyl lithium (2.84 mL, 7.1 mmol, 2.5 M solution in hexane) was slowly added to a solution of 2,4-dimethoxy-6-methylbenzamide (650 mg, 3.1 mmol) in THF ( 30 ml) under nitrogen with cooling (ice-salt bath), keeping the temperature below 20 ° C. After the addition was complete, the mixture was stirred for 1 h. at 0 ° C and then cooled to -50 ° C and a solution of 4- (2-tert-butyldimethylsilanyloxy) -ethoxy) -3,5-dimethylbenzonitrile (block forming ring B, above) (996 mg, 3.26 mmol) in THF (10 mL). The cooling bath was removed, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. in room temperature. Saturated NH4Cl solution was added with cooling, and then the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give 1.2 g of crude product.

[0109] The above crude product (1.2 g) was treated with ethanol (10 mL) and conc. HCl (2 ml) at 80 ° C for 1 hour The solvent was removed, the residue was dissolved in methanol and neutralized with NaHCO3. The solvent was evaporated and the crude product was purified by column chromatography to give 3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one (100 mg, 11%). Selected data: MP 193-195 ° C.

Example 3 (Reference example) [0110]

<img file="PL2118074T3_D0015.tif" />

3- (4-hydroxy-3,5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one [0111] Hydrogen bromide in acetic acid (13 ml, 33% by weight) was added to the mixture of 2-methylbenzoic acid (4.08 g, 30 mmol), paraformaldehyde (2.50 g, 83.0 mmol) and o-phosphoric acid (7 mL, 85%). The reaction mixture was stirred at 115 ° C for 15 hours. It was cooled to room temperature and poured into ice water. A white precipitate formed. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 ml), brine (100 ml) and dried over anhydrous Na2SO4. Removal of the solvent gave 6.84 g of a white solid which was used in the next step without further purification. The above compound (6.8 g) was dissolved in anhydrous dichloromethane (150 mL). Oxalyl chloride (7.8 mL) was added dropwise. After the addition, 3 drops of anhydrous DMF were added. An intense reaction occurred and stirring was continued overnight. The solvent and excess oxalyl chloride were removed under reduced pressure, and the residue was dried in vacuo to give 7.02 g of a brown liquid, which was used in the next step without further purification. The above compound (7.02 g, 28.36 mmol) was dissolved in anhydrous THF (60 mL) and cooled to 0 ° C. A solution of N-methylamine (2.0 M in THF, 19 mL, 38.03 mmol) was added dropwise under a nitrogen atmosphere. Mixing continued for 15 min. at 0 ° C. The ice bath was removed and stirring was continued at room temperature for 3 hours. A white precipitate formed. Water (100 ml) was added and the mixture was extracted with ethyl acetate (150 ml). The organic layer was separated, washed with water (50 ml), saturated NaHCO3 solution (2x50 ml), water (50 ml) and brine (50 ml) and dried over anhydrous Na2SO4. Removal of the solvent gave 5.64 g of 5-bromomethyl-2, N-dimethylbenzamide as a white solid which was used in the next step without further purification. To a solution of the above compound (2.42 g, 10 mmol) in anhydrous THF was added morpholine (1.92 g, 22 mmol) at room temperature under a nitrogen atmosphere. A white precipitate formed. Stirring continued overnight. Water (100 ml) was added and the mixture was extracted with ethyl acetate (150 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml) and dried (Na2SO4). Removal of the solvent gave a colorless oil that was purified by column chromatography (silica gel, sieve number 230-400; 0-5% methanol in CH2Cl2 as eluent) to give the desired intermediate as a benzamide (yield 0.50 g, twenty%). N-butyl lithium (1.6 M solution in hexane, 4.1 mL, 6.6 mmol) was added dropwise to a solution of benzamide (0.5 g, 2.0 mmol) in anhydrous THF (4 mL) at -10 ° C within 10 min. under a nitrogen atmosphere. Stirring was continued at 0 ° C for 1 hour. The reaction mixture was cooled to -50 ° C. A solution of 4- (tert-butyldimethylsilanyloxy) -3,5-dimethylbenzonitrile (0.653 g, 2.5 mmol in anhydrous THF (3 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperature for 1 hour. Aqueous ammonium chloride (5 mL) was added, followed by the addition of ethyl acetate (50 mL). The organic layer was separated, washed with water (5 ml) and dried (Na2SO4). After removal of the solvent, 1.23 g of a light yellow viscous material was obtained, which was used in the next step without further purification. The above compound (1.2 g) was dissolved in 10 mL of anhydrous ethanol. Conc. HCl (1 mL) and the mixture was heated to reflux for 15 min and then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was made basic with a solution of ammonia in methanol and purified by column chromatography (silica gel, sieve number 230-400, 0-5% methanol in CH2Cl2 as eluent) to give 3- (4-hydroxy-3,5-dimethylphenyl) ) -7-morpholine-4-methyl-2H-isoquinolin-1-one (35 mg) as a white solid (free

1205 principle). To a solution of the above compound (35 mg) in CH 2 Cl 2 (5 mL) and MeOH (1 mL) was added dropwise a solution of hydrogen chloride in ether (0.5 mL, 1.0 M) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried in vacuo to give 3- (4-hydroxy-3,61210 dimethylphenyl) -7- (morpholinomethyl) isoquinolinone-1 (2H) -one hydrochloride (36 mg, 93%) as a yellow solid. Selected data: MP 281-283 ° C (hydrochloride).

Example 4

1215 [0112]

<img file="PL2118074T3_D0016.tif" />

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1220 [0113] A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-neck flask was cooled to 0 ° C. HCl gas (227 g) was bubbled through the solution for 45 min. After 45 min. at 10 ° C, the mixture was filtered, washed with isopropylacetate (4 L) and dried overnight under high vacuum at 45 ° C to give the hydrochloride (242.3

1225 g, 98%) as a white solid. The above mixture of hydrochloride (20 g, 0.105 mol) and oxalyl chloride (33 ml) in a 3-neck flask equipped with a reflux condenser was heated for 2 hours. with stirring (external temperature 170 ° C) and oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0 ° C and methanol (40 mL) was added.

The reaction mixture was heated to reflux for 45 min, filtered hot and washed with methanol (80 ml) to give 4,6-dimethoxyisatin (17.2 g, 79%) as a yellow-green solid. To the heated solution (external temperature 70 ° C) isatin (182 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added slowly H2O2 (35%, 405 mL) over 2 hours. After adding each portion of H2O2, the internal reaction temperature (initially 64 ° C) increased (to a maximum temperature of 80 ° C). After the addition was complete, the foaming reaction mixture was stirred for an additional 2 hours. at 70 ° C and the reaction mixture was allowed to continue stirring overnight while cooling to room temperature. The mixture was heated to 70 ° C. Additional H2O2 (75 mL) was added and the reaction mixture was stirred at 70 ° C for a further 2 hours until the reaction was complete. After cooling to 10 ° C (bath temperature), an aqueous Na2S2O3 solution (150 mL, saturated solution) was added. The mixture was adjusted to pH 8 with HCl (37%, 1.6 L) and pH 6 with acetic acid (crystallized, 75 mL), not allowing the reaction mixture to warm to a temperature higher than 40 ° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a light brown solid (83.7 g, 55%). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCI (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol) and NMM ( 51.3 ml) and the reaction mixture was allowed to stir at room temperature for 3 hours. Aqueous NH3 (83 mL, 50%) was added and the mixture was stirred at room temperature for 16 hours. Water (1.25 L) was added and the mixture was extracted with DCM (2x250 mL). The combined extracts were then washed with water (2x500 ml). Concentration, suspension in ether (550 mL), filtration and drying under high vacuum gave 2-amino-4,8-dimethoxybenzamide (46.7 g, 57%) as a brown solid.

[0114] 2-Amino-4,8-dimethoxybenzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol ) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80 ° C for 12 hours. It was cooled to room temperature and poured onto crushed ice. The solid was collected and purified by column chromatography to give 2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.9 g, 51%) as a white solid.

1265 Selected data: MP 291-293 ° C.

Example 5 (Reference example) [0115]

1270

<img file="PL2118074T3_D0017.tif" />

3- (4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,81275 dimethoxyisoquinolin-1 (2H) -one [0116] To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2, 00 g, 13.5 mmol) and

1-chloro-2-methylpropan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 ml) potassium carbonate (7.5 g, 54 mmol) and water (5 ml) were added. The reaction mixture was stirred at reflux for 1280 h. and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL) and dried over anhydrous Na 2 SO 4. Removal of the solvent gave 4- (2-hydroxy-2-methylpropoxy) -3.51285 dimethylbenzonitrile (2.9 g, 97%) as a white solid.

[0117] To a solution of 4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylbenzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol ) and tert-butyldimethylsilyl chloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 days. Water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water (2x100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4 [2- (tert-butyldimethylsilanyloxy) -2-methyl-propoxy] -3,5-dimethylbenzonitrile (2.24 g, 54%). N-butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added dropwise to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 ml) at -10 ° C for 10 min. under a nitrogen atmosphere. Stirring was continued at 0 ° C for 1 hour. The reaction mixture was cooled to -50 ° C. The solution was added quickly

4- (tert-butyldimethylsilanyloxy) -3,5-dimethylbenzonitrile (1.68 g, 4.73 mmol) in anhydrous THF (6 mL). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperature for 1 hour. Aqueous ammonium chloride (10 mL) was added, followed by the addition of ethyl acetate (100 mL). The organic layer was separated, washed with water (10 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel, sieve number 230-400, 0-6% methanol in CH 2 Cl 2 as eluent) to give 3- {4- [2- (tert-butyldimethylsilanyloxy) -2-methylpropoxy] -3,5-dimethylphenyl} -6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%) as a white solid.

[0118] The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 mL). Tetrabutylammonium fluoride (4.1 mL, 1.0 M solution in THF) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min, then at room temperature for 2 hours, and then stirred at 70 ° C for 24 hours. The mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (30 ml) was added. The organic layer was separated, washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Raw Product

1320 purified by column chromatography (silica gel, sieve number

230-400; 0-4% methanol in CH2Cl2 as the eluent), yielding 3- (4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one (0.15 g, 46%) as a white solid. Selected data: MS (ES) m / z: 397.98;

MP 252-254 ° C at decomposition.

1325

Example 6 (Reference example) [0119]

<img file="PL2118074T3_D0018.tif" />

7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-natphyridin-5 (6H) -one [0120] Malonic acid mixture (20 g, 192 mmol), 2.4, 6-trichlorophanolu

1335 (72 g, 365 mmol) and phosphorus oxychloride (38 ml, 403.2 mmol) were stirred at reflux for 12 hours. The reaction mixture was cooled to 70 ° C and poured into ice water. The solid was collected by filtration, washed with water and dried to give malonic bis (2,4,6-trichlorophenyl) ester (85 g, 95%). A solution of bis1340 (2,4,6-trichloro-phenyl) ester of malonic acid (85 g, 184 mmol) and ethyl 3-aminoconate (26.08 g, 201.9 mmol) in bromobenzene (100 mL) was stirred at reflux temperature. for 50 min.

The reaction mixture was cooled to 50 ° C and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water and dried to give 4,6-dihydroxy-2-methyl-nicotinic acid ethyl ester (31 g, 86%). A solution of 4,6-dihydroxy-2-methylnicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (80 mL, 629 mmol) was stirred at reflux for 1.5 hours. Excess phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3x100 mL) and concentrated. The residue was further purified by column chromatography to give 4,6-dichloro-2-methyl-nicotinic acid ethyl ester (16.9 g, 46%). Acid ethyl ester solution

4,6-dichloro-2-methylnicotinic (16.9 g, 71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL, 258.68 mmol) and stirred at reflux for 12 hours. . The reaction was quenched by the addition of HOAc (50 mL). The mixture was diluted with water (200 mL), extracted with dichloromethane (3x100 mL) and concentrated. The residue was purified by column chromatography (SiO2, hexanes / EtOAc = 6: 1) to give 4,6-dimethoxy-2-methylnicotinic acid methyl ester (10 g, 87%). A solution of 4,6-dimethoxy-2-methylnicotinic acid methyl ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g, 44.08 mmol) in water (40 ml), MeOH (30 ml) and THF (20 mL) was stirred at reflux for 4 hours. The reaction mixture was concentrated to dryness. The residue was mixed with HCl (conc., 20 mL) and again concentrated under high vacuum to dryness to afford crude 4,6-dimethoxy-2-methylnicotinic acid (quantitative yield). To a solution of 4,6-dimethoxy-2-methylnicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h, concentrated to dryness on a rotary evaporator to give crude 4,6-dimethoxy-2-methylnicotinic acid HCl chloride salt (2.8 g, quantitative). A solution of 4,6-dimethoxy-2-methylnicotinic acid HCl chloride salt (4.8 g, 23.5 mmol) in dichloromethane (100 mL) at room temperature was poured into an ammonium hydroxide beaker (200 mL). The reaction mixture was stirred at room temperature for 1 h, extracted with dichloromethane (3x100 mL) and concentrated on a rotary evaporator to give 4,6-dimethoxy-2-methylnicotinamide (2.4 g, 52%) as a light yellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.59 mmol) in DMF (20 mL) at room temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.82 mL, 13.59 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of water (200 mL), extracted with EtOAo (3x100 mL) and concentrated. The residue was purified by column chromatography to give 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%) as a white solid. To a solution of 4,6-dimethoxy-2-methylnicotinamide (1 g, 5.1 mmol) in THF (120 mL) at -20 ° C was added n-BuLi (9.6 mL,

15.3 mmol). The reaction mixture was stirred at -20-0 ° C for 2.5 hours and then cooled to -78 ° C. 4-benzyloxy-3,5-dimethylbenzonitrile (1.21 g, 5.1 mmol) was added, the cooling bath was removed and the reaction mixture was allowed to warm gradually to room temperature. After stirring at room temperature for 20 hours. the reaction was quenched by the addition of water (100 ml), extracted with dichloromethane (3x100 ml) and concentrated on a rotary evaporator. The residue was further purified by column chromatography (SiO2, hexanes / EtOAc / MeOH = 3: 2: 1) to give 7- (4-benzyloxy-3,5-dimethylphenyl) -2,4-dimethoxy- [1,6] naphthyridin- 5-ylamine (0.4 g, 19%) and 7- (4-benzyloxy-3,5-dimethylphenyl) -2,4-dimethoxy-6H [1,6] naphthyridin-5-one (0.34 g, 16%). A solution of 7- (4-benzyloxy-3,5-dimethylphenyl) -2,4-dimethoxy-6H- [1,6] naphthyridin-5-one (0.34 g, 0.82 mmol) in DMF (100 ml) and MeOH (100 ml) mixed with palladium / carbon (0.1 g) and hydrogenated (50 psi) for 2 h The mixture was filtered through a Celite pad. The filtrate was concentrated under high vacuum to give 7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-6H [1,6] naphthyridin-5-one (0.23 g, 88%) . A solution of 7- (4-hydroxy-3,5-dimethylphenyl) 2,4-dimethoxy-6H- [1,8] naphthyridin-5-one (0.23 g, 0.7 mmol) in MeOH (20 mL) and

DCM (20 ml) was mixed with HCl in ether (7 ml, 7 mmol) and stirred for 0.5 h. The reaction mixture was concentrated on a rotary evaporator to give a dry residue. The solid was rinsed with DCM, filtered off, washed

DCM to give 7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,61410 naphthyridin-5 (6H) -one HCl salt (0.15 g, 59%) as a light yellow solid . Selected data: MS (ES) m / z: 327.06; MP&gt; 324 ° C at decomposition (HCl salt).

Example 7

1415 [0121]

<img file="PL2118074T3_D0019.tif" />

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1420 [0122] A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4- [2- (tert-butyldimethylsilanoxy) ethoxy] -3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol ) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C for 1 hour. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70 ° C for 16 hours. A mixture of

1425 the reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2SO4. Removal of the solvent gave a crude product which was purified by column chromatography to give 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyisoquinolin-4 (3H) -one (444 mg, 39%) in form

1430 white solid. Selected data: 229-231 ° C.

[0123] Optionally, 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4- (3H) -one can be synthesized by the following method. 3,5-dimethyl-4-hydroxybenzaldehyde (26.9 g, 0.179) was placed in a dry 2 L round-bottom flask with a reflux condenser and magnetic stirrer.

1435 mol) in ethanol (350 ml). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed

1440 water, brine and dried over Na2SO4. After removal of the solvent, 45 g of crude product was obtained. The crude product was purified by column chromatography (silica gel, sieve number 230-400, ethyl acetate in hexane as eluent) to obtain 33.3 g (9596) of product. To a solution of 2-amino-4,6-dimethoxybenzamide (33.45 g, 0.170 mol) and 4- (2-hydroxyethoxy) -3.51445 dimethylbenzaldehyde (33.3 g, 0.170 mol) in N, N-dimethylacetamide (300 ml) , NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150 ° C for 14 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min. in

1450 room temperature. The separated solids were filtered off and dried to give the crude product. The crude product was purified by column chromatography (silica gel, sieve number 230-400; 5% methanol in CH 2 Cl 2 as eluent) to give 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) 5,7-dimethoxyquinazolin-d (3H) -one (33 g, 52%).

1455

Example 8 (Reference example) [0124]

<img file="PL2118074T3_D0020.tif" />

3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one [0125] Compound 3- [4- (2- chloroethoxy) -3,5-dimethylphenyl] -6,8-dimethoxyisochromen-1-one (298 mg, 0.767 mmol) was dissolved in DMSO (5 ml) and N-methylpiperazine (388 mg, 3.83 mmol) and Et3N ( 392 mg, 3.83 mmol). The reaction mixture was heated at 110 ° C for 16 hours, then cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo to give a residue which was purified by column chromatography. The yield was 60 mg (17%). 3- [3,5-Dimethyl-4- (2-4-methylpiperazin-1-yl-ethoxy) phenyl) -8,8-dimethoxy-isochromen-1-one compound (60 mg, 0.13 mmol) and solution NH3 (2.0

M solution in ethanol, 20 ml) was stirred in a steel bomb and heated at 130 ° C for 16 hours. The solvent was removed and the crude compound was purified by column chromatography. The compound was then converted into 3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one hydrochloride salt (40 mg, 62% ), as an off-white solid. Selected data: MS (ES) m / z: 452.1; MP 195-198 ° C (HCl salt).

Example 9 [0126]

<img file="PL2118074T3_D0021.tif" />

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1490 [0127] 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4- (3H) -one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-hydroxy-3-metaxybenzaldehyde by the method described for 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one, resulting in the isolation of 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (90 mg, 36%) in white form

1495 solid substance. Selected data: MS (m / z): 329.06; MP 294-296 ° C.

Example 10 [0128]

1500

<img file="PL2118074T3_D0022.tif" />

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1505 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) he was synthesized from 2-amino-4,6-dimethoxybenzamide and 4- [bis- (2-hydroxyethyl) ) -amino] -benzaldehyde, by the method described for 5,7-dimethoxy-263 (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) 5,7-dimethoxyquinazolin-4 (3H) -one (120 mg, 41%) was isolated as a yellow solid. Selected data: MS (m / z): 386.15; MP 249-251 ° C.

Example 11 [0130]

1515

<img file="PL2118074T3_D0023.tif" />

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one

1520 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) he was synthesized from 2-amino-4,5-dimethoxybenzamide and 4- (N, N- bis (2-hydroxyethyl) amino) benzaldehyde, by the method described for 5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxy-quinazolin-4 (3H) -one (72 mg, 24%) was isolated in the form of yellow

1525 solid substance. Selected data: MS (m / z): 386.15; MP 268-270 ° C.

Example 12 [0132]

1530

<img file="PL2118074T3_D0024.tif" />

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one

1535 [0133] 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin4 (3H) -one was synthesized from 2-amino-4,5-dimethoxybenzamide and 2, 3dihydrobenzo [1,4] dioxine-6-carbaldehyde, by the method described for 5,7-dimethoxy2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6yl) -6,7-dimethoxyquinazolin-4 (3H) -one (180 mg, 69%) was isolated as

1540 a light yellow solid. Selected data: MS (m / z): 341.03; MP 316,4318,2 ° C.

Example 13

1545 [0134]

<img file="PL2118074T3_D0025.tif" />

2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1550 [0135] To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 hours in room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate.

The combined organic layers were washed with water, brine and dried over Na2SO4.

The solvent was removed to give 4.61 g of crude 4- (4-ethylpiperazin-1-ylmethyl) benzoic acid ethyl ester (100% yield). Lithium aluminum hydride (0.792 g, 20.86 mmol) was placed in a dry 3-neck flask and THF (60 ml) was added while cooling. A solution of 4- (4-ethyl-piperazin-1-ylmethyl) -benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly while cooling. After the addition, the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to 0 ° C, 10% NaOH solution was added, followed by the addition of water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude 4- (4-ethyl-piperazin-1-ylmethyl) -phenyl) -methanol (78% yield). To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to -78 ° C, oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at -78 ° C. A solution of 4- (4-ethyl-piperazin-1-methyl) phenyl) methanol (2.78 g, 11.88 mmol) in CH 2 Cl 2 (10 mL) was added at -78 ° C and stirred at -78 ° C for 1 hour. . Then Et3N (4.8 g, 47.52 mmol) was added at -78 ° C. The reaction mixture was allowed to warm to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was then removed to give crude 4- (4-ethylpiperazin-1-ylmethyl) benzaldehyde (2.5 g, 91%).

[0136] To a solution of 2-amino-4,8-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4- (4-ethyl-piperazin-1-ylmethyl) benzaldehyde (177 mg, 0.76 mmol) in N , N-dimethylacetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150 ° C for 5 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with a NaHCO3 solution. The solvent was removed under reduced pressure to give a crude product which was purified by column chromatography to give 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxy-quinazolin-4 (3H) -one ( 87 mg

1590 27%), which was converted into the hydrochloride salt. Selected data: MS (ES) m / z: 409.11; MP 278-280 ° C (with decomposition).

Example 14

1595 [0137]

<img file="PL2118074T3_D0026.tif" />

1600 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrido [2,3-d1-pyrimidin-4 (3H) -one [0138] For 2-amino-4,6-dimethoxy-solution nicotinamide (1.07 g, 5.42 mmol) and

4- [2- (tert-butyldimethylsilanoxy) ethoxy1-3.5-dimethylbenzaldehyde (1.67 g,

1605 5.42 mmol) in N, N-dimethylacetamide (25 mL), NaHSO3 (1.06 g, 5.97 mmol) and p-TSA (1.14 g, 5.97 mmol) were added and the reaction mixture was heated at 150 ° C for 16 hours, cooled to room temperature and poured into water. The solid was collected to give 3.25 g of crude product.

To a solution of the crude product (3.25 g, 6.70 mmol) in THF (50 mL) was added 1610 TBAF (3.6 g, 13.4 mmol) at 0 ° C and the reaction mixture was stirred at room temperature for 1 hour. . The reaction mixture was quenched with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed and the crude product was purified by method

1615 column chromatography (silica gel, sieve number 230-400; 2% methanol in CH2Cl2 as eluent), yielding 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) 5,7-dimethoxypyrido [2,3-d ] pyrimidin-4 (3H) -one (132 mg, 6%). Selected data: MS (ES) m / z: 371.99: MP 255-256 ° C.

1620 Example 15 [0139]

<img file="PL2118074T3_D0027.tif" />

1625

2- (2-chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one [0140] According to the method described for 5,7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one, 2- (2-chloro-61630 methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4,6-dimethoxybenzamide and chloride 2 -chloro-6-methyl-isonicotinoyl in 75% yield as a white solid. Selected data:¹H NMR (300 MHz, CDCl3) δ 10.95 (s, 1H), 7.90 (s, 2H), 6.74 (d, J = 2.33 Hz, 1H), 6.51 (d, J =

2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H); MS (APCI) m / z 332

1635 [M + H] +.

Example 16 [0141]

<img file="PL2118074T3_D0028.tif" />

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one [0142] To a solution of 4-methoxy-3,5-dimethylbenzoic acid (0.100 g, 0.555 mmol) in CH2Cl2 (2.77 mL) cooled to 0-5 ° C added oxalyl chloride (67.8 ul, 0.777 mmol) followed by DMF dropwise (4.3 mL, 0.056 mmol). The reaction mixture was stirred for 50 min, volatiles removed in vacuo and the crude acid chloride was used directly without further purification.

[0143] To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.566 mmol) and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise a solution of acid chloride (crude the residue is described above) in THF (925 μϋ). After 16 h, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (3x75 mL), saturated aqueous NaHCO3 (3x75 mL) and brine (75 mL). An insoluble yellow solid was isolated by filtration to give an amide (0.150 g, 83%). A mixture of amide (0.148 g, 0.413 mmol) and 2M NaOH (7.00 mL) was heated at 85 ° C for 19 hours, cooled to 5 ° C and neutralized with a 4M HCl solution in dioxanes. The white solid was filtered off and rinsed with acetone to give 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one (0.144 g, 100%). Selected data:¹H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J = 2.33 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H); MS (APCI) m / z 341 [M + H] +.

Example 17 [0144]

1670

<img file="PL2118074T3_D0029.tif" />

2- (4-Amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one [0145] To 3,5-dimethyl-4-nitrobenzoic acid solution (1.00 g, 5.12

1675 mmol) in CH2Cl2 (25.6 mL) cooled to 0-5 ° C, oxalyl chloride (0.626 mL, 7.17 mmol) was added followed by DMF dropwise (39.8 μΕ). The reaction mixture was stirred for 2 h, the volatiles removed in vacuo and the crude acid chloride was used directly without further purification. To a mixture of 2-amino-4,6-dimethoxybenzamide (0.913 g, 4.65

1680 mmol) and pyridine (414 μΕ, 5.12 mmol) in THF (18.6 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (8.53 mL). After 16 h, the reaction mixture was diluted with EtOAc (500 mL), washed with saturated aqueous NH4Cl (3x100 mL), saturated aqueous NaHCO3 (3x100 mL) and brine (100 mL). Insoluble yellow solid

1685 isolated by filtration to give an amide (1.51 g, 87%). A mixture of amide (1.50 g, 4.03 mmol) and 2M aqueous NaOH (25.0 mL) was heated at 85 ° C for 17 hours, then THF (50 mL) was added and stirred at reflux. feedback for 25 hours The volatiles were removed in vacuo, the mixture was cooled to 5 ° C and neutralized

1690 solution of 4M HCl in dioxanes. After stirring for 30 min, the white solid was filtered and lyophilized with MeCN / H2O to give the cyclized compound (1.36 g, 95%). A mixture of the cyclized compound (0.200 g, 0.563 mmol), Na2S2O4 (0.980 g, 5.63 mmol), water (5.00 mL) and MeOH (15.0 mL) was stirred at 70 ° C for 2 hours. Volatiles were removed in vacuo then 1695 diluted with ethyl acetate (200 mL), washed with saturated NaHCO3 (2x100 mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered and the volatiles removed in vacuo to give 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.062 g, 34%) as yellow solid substance. Selected data:¹H NMR (300 MHz, DMSO-d6) δ 11.45 (s,

1700 1H), 7.78 (s, 2H), 6.66 (d, J = 2.25 Hz, 1H), 6.42 (d, J = 2.24 Hz, 1H), 5.26 (s,

2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.14 (s, 6H); MS (APCI) m / z 326 [M + H] +.

Example 18

1705 [0146]

<img file="PL2118074T3_D0030.tif" />

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,61710 dimethylphenoxy) ethyl) -N2-methylphthalamide (left) and 2- (4 - (2-aminoethoxy) 3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (right) [0147] Mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol ), N- (2-bromoethyl) -phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol),

1715 Nal (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1M NaOH (2x100 mL), 1M HCl (2x100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, hexanes / EtOAc) to give the expected ether (0.300 g,

23%) as a yellow solid. A mixture of the above ether (0.293 g,

0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol) and p-TsOH * H2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 hours and then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3x75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, CH2Cl2 / CH3OH) to give the expected product (0.076 g, 17%) as a light yellow solid.

A mixture of the above compound (0.213 g, 0.426 mmol) and 2M methylamine w

THF (25.0 mL) was stirred at room temperature for 17 hours. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography to give N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493 g, 22%) and 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one compound (0.0360 g , 23%) as white solids. Selected data for N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazoline-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide: ¹H

NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.51 (t, J = 5.57 Hz, 1H), 8.18 (q, J = 4.57 Hz, 1H ), 7.89 (s, 2H), 7.63-7.42 (m, 4H), 6.74 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2, 29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J = 5.73 Hz, 2H), 2.71 (d, J = 4.62 Hz, 3H ), 2.32 (s, 6H): MS (APCI) m / z 531 [M + H] +. Selected data for 2- (4- (2aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one:¹H NMR (300 MHz, DMSO-d6) δ 7.90 (s, 2H), 6-74 (d, J = 2.31 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H ), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J = 5.76 Hz, 2H), 2.91 (t, J = 5.75 Hz, 2H ), 2.30 (s, 6H); MS (APCI) m / z 370 [M + H] +.

Example 19 [0148]

<img file="PL2118074T3_D0031.tif" />

1755 N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide. Mixture 2- (4- ( 2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.060 g, 0.162 mmol), 41760 methoxybenzenesulfonyl chloride (0.044 mg, 0.211 mmol) and triethylamine (29.4 μΐ, 0.211 mmol ) in CH₂cl₂ (812 μί) was stirred at room temperature for 3 hours. The mixture was chromatographed directly on silica gel to give N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide ( 0.046 g, 53%) in the form

1765 white solid after lyophilization with MeCN / H2O. Selected data:¹H NMR (300 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17-7, 07 (m, 2H), 6.73 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H), 3.91-3.75 (m, 11 H), 3.12 (q, J = 5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m / z 540 [M + H] +.

1770 Example 20 [0150]

<img file="PL2118074T3_D0032.tif" />

4-chloro - \ - (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide [0151] According to the method described for N - (2- (4- (5,7-dimethoxy-4-oxo-3,4dihvdrochinazolin-2-yl) -2,6-Dimethylphenoxy) ethyl) -4metoksvbenzenosulfonamidu. 4-chloro-N- (2- (4- (5.7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide from 2- (4- (2- aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 51% yield and was isolated as a white solid after lyophilization with MeCN / H2O. Uploaded data:¹H NMR (300 MHz, DMSO-d6) δ ppm 11.8 (s, 1H), 8.1 (s, 1H), 7.9 - 7.6 (m, 6H), 6.75 (1H ), 6.5 (1H), 3.9 - 3.7 (m, 8H), 3.15 (m, 2H), 2.2 (s,

6H); MS (APCI) m / z 544 [M + H] +.

Example 21 [0152]

<img file="PL2118074T3_D0033.tif" />

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide [0153] A mixture of 3,5-dimethyl 4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N- (2-bromoethyl) phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), Nal (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1M NaOH (2x100 mL), 1M HCl (2x100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, hexanes / EtOAc) to give the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol) and p-TsOH * H2O (0.0173 g , 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 hours and then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3x75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, CH2Cl2 / CH3OH) to give the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2M methylamine in THF (25.0 mL) was stirred at room temperature for 17 hours. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography to give N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493 g, 22%) and 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one compound (0.0360 g , 23%) as white solids. Selected data for N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide: ¹H

NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.51 (t, J = 5.57 Hz, 1H), 8.18 (q, J = 4.57 Hz, 1H ), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2, 29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J = 5.73 Hz, 2H), 2.71 (d, J = 4.62 Hz, 3H) , 2.32 (s, 6H); MS (APCI) m / z 531 [M + H] +.

Example 22 [0154]

<img file="PL2118074T3_D0034.tif" />

1835

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide. Mixture 2- (4- ( 2-aminoethoxy) -3,5-dimethylphenyl) -5,71840 dimethoxyquinazolin-4 (3H) -one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044 mg, 0.211 mmol) and triethylamine (29.4 μΐ, 0.211 mmol ) in CH₂cl₂ (812 μί) was stirred at room temperature for 3 hours. The mixture was chromatographed directly on silica gel to give N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2.61845 dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization with MeCN / H2O. Selected data:¹H NMR (300 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17-7, 07 (m, 2H), 8.73 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H), 3.91-3.75 (m, 11 H), 3.12 (q, J = 5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m / z 540 [M + H1 +.

1850

Example 23 [0156]

1855

<img file="PL2118074T3_D0035.tif" />

4-Chloro-A- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihvdrochinazolin-2-yl) -2,6dimetylofenoksy) ethyl) benzenesulfonamide

1860

1865

1870 [0157] According to the method described for N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide, compound 4 was obtained -chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide from 2- (4- (2-aminoethoxy) - 3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 51% yield and was isolated as a white solid after lyophilization with MeCN / H2O. Uploaded data:¹H NMR (300 MHz, DMSO-d6) δ ppm 11.8 (s, 1H), 8.1 (s, 1H), 7.9-7.6 (m, 6H), 6.75 (1H ), 6.5 (1H), 3.9-3.7 (m, 8H), 3.15 (m, 2H), 2.2 (s, 6H); MS (APCI) m / z 544 [M + H] +.

Example 24 [0158]

1875

<img file="PL2118074T3_D0036.tif" />

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihvdrochinazolin-2-yl) -2,6dimetylofenoksy) ethyl) methanesulfonamide

1880 [0159] According to the method described for N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide, compound N - (2- (4- (5,7-dimethoxy-477 oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide with 2- (4- (2-aminoethoxy) -3 , 5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

1885 in 42% yield and isolated as a white solid after freeze drying with MeCN / H2O. Selected data:¹H NMR (300 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 7.90 (s, 2H), 7.33 (t, J = 5.94 Hz, 1H), 6.74 ( d, J = 2.31 Hz, 1H),

6.52 (d, J = 2.30 Hz, 1H), 3.92-3.81 (m, 8H), 3.41-3.34 (m, 2H), 2.97 (s, 3H) .

2.32 (s, 6H); MS (APCI) m / z 448 [M + H] +.

1890

Example 25 [0160]

<img file="PL2118074T3_D0037.tif" />

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl propylcarbamate

1900 [0161] A mixture of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.070 g, 0.19 mmol), propyl isocyanate (0.088 ml, 0, 94 mmol) and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70 ° C for 16 hours. The mixture was filtered, washed with THF and the solvent removed under reduced pressure. The residue was dissolved

1905 in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent removed under reduced pressure. The resulting solid was chromatographed on silica gel to give 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,8-dimethylphenoxy) ethyl propylcarbamate (0.035 g, 41%) as an off-white solid. Selected data:¹H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J = 5.27 Hz, 1H), 6.74 (d , J = 2.32 Hz, 1H), 6.52 (d,

J = 2.31 Hz, 1H), 4.27 (t, J = 4.29 Hz, 2H), 3.99 (t, J = 4.29 Hz, 2H), 3.89 (s, 3H) .

3.84 (s, 3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J = 7.33

Hz, 3H); MS (APCI) m / z 456 [M + H] +.

Example 26 [0162]

<img file="PL2118074T3_D0038.tif" />

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate [0163] According to the method described for 2- (4- (5, propylcarbamate 7dimetoksy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate compound from 2- (4- (2-hydroxyethoxy) 3.5 -dimethylphenyl) -5,7-dimethoxy quinazolin-4 (3H) -one in 11% yield and was isolated as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.08 (m, 1H), 6.74 (d, J = 2.29 Hz , 1H),

6.52 (d, J = 2.27 Hz, 1H), 4.27 (t, J = 4.55 Hz, 2H), 3.99 (t, J = 4.55 Hz, 2H), 3, 89 (s, 3H), 3.84 (s, 3H), 2.60 (d, J = 4.57 Hz, 3H), 2.29 (s, 6H); MS (APCI) m / z 428 [M + H] +.

Example 27 [0164]

1940

<img file="PL2118074T3_D0039.tif" />

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -4-methyl-benzamide

1945 [0165] A mixture of 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.060 g, 0.16 mmol), p-toluyl chloride (0.028 ml) , 0.21 mmol) and PS-DIEA (0.057 g, 0.21 mmol) in CH 2 Cl 2 (4.0 mL) was stirred at room temperature for 16 hours. The mixture was filtered, washed with CH2Cl2 and the solvent removed under reduced pressure.

1950 The obtained residue was subjected to silica gel chromatography to obtain N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide ( 0.037 g, 51%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.80-11,00 (s, 1H), 8.69 (t, J = 5.43 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J = 8.19 Hz, 2H), 7.28 (d, J = 8.00 Hz, 2H),

1955 6.73 (d, J = 2.31 Hz, 1H), 6.51 (d, J = 2.31 Hz, 1H), 3.94 (t, J = 5.59 Hz, 2H),

3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m / z 488 [M + H] +.

Example 28

1960 [0166]

<img file="PL2118074T3_D0040.tif" />

1965 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate [0167] A mixture of 4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenol (0.100 g, 0.270 mmol), cyclohexyl isocyanate (172 μL, 1.35 mmol) and Et₃N (263 μL,

1970 1.89 mmol) in THF (1.00 mL) was stirred at reflux for 4 hours, then diluted with EtOAc (200 mL) and washed with saturated aqueous ammonium chloride (3 x 75 mL) and brine (75 mL ). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on gel

1975 silica (12 g, CH2Cl2 / CH3OH) and the product was lyophilized from MeCN / H2O to give 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate (0.0981 g, 73%) as a white solid. ¹H NMR (300 MHz, DMSO - ^, δ) 11.82 (s, 1H), 7.90 (s, 2H), 7.24-7.05 (m, 1H), 6.73 (d, J = 2.30 Hz, 1H), 6.52 (d, J = 2.31 Hz, 1H),

1980 4.30-4.22 (m, 1H), 4.03-3.95 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 6H),

1.82-1.46 (m, 5H), 1.18 (m, 5H); MS (APCI) m / z 496 [M + H] +.

Reference example A

1985 [0168]

<img file="PL2118074T3_D0041.tif" />

4- (2- (4- (6,8-dimetoksvizochinolin-3-yl) -2,6-Dimethylphenoxy) ethyl) morpholine

1990 [0169] To a solution of 4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphanol (0.309 g, 1.0 mol) in anhydrous THF (20 ml), triphenylphosphane (0.52 g, 2 , 0 mmol), 4- (2-hydroxyethyl) morpholine (0.262 g, 2.0 mmol) and N, N-diisopropylethylamine (0.387 g, 3.0 mmol). To this mixed solution

1995 diethyl azadicarboxylate (0.348 g, 2.0 mmol) was added. The reaction mixture was stirred at room temperature overnight under nitrogen, after dilution with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by chromatography

2000 column and 3- [3,5-dimethyl-4-2-morpholin-4-vethoxy) phenyl] -6,8-dimethoxyquinoline (0.54 g) was obtained as a white solid.

[0170] To a solution of the above compound (0.54 g, impure) in a 1: 1 mixture of ether with CH2Cl2 (10 mL), 1.0 M hydrogen chloride in ether (2 mL) was added, and the reaction mixture was stirred at room temperature for

2005 30 minutes. The solvent was removed under reduced pressure. The residue was triturated using 10% methanol in ether to afford 4- (2- (4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenoxy) ethyl) morpholine (0.323 g,

70% in two stages) as a yellow solid. Selected data: MS (ES) m / z: 423.1; MP 239-240 ° C (HCl salt).

2010

Example 29 [0171]

<img file="PL2118074T3_D0042.tif" />

N- (2- (4- (5.7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2.6dimetylofenoksy) ethyl) benzenesulfonamide

2020 [0172] According to the method described for reference example A, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 41% yield and was isolated it as an off-white solid. MS (APCI) m / z 510 [M + H] +.

2025 Example 30 [0173]

<img file="PL2118074T3_D0043.tif" />

2030

N- (2- (4- (5.7-dimethoxy-4-oxo-3.4-dihydroquinazolin-2-yl) -2.6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide [0174] According to the method described for Reference Example A, the title compound 2035 made from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 50% yield and isolated as an off-white solid. MS (APCI) m / z 524 [M + H] +.

Reference example B [0175]

<img file="PL2118074T3_D0044.tif" />

5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one [0176] To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in

N, N-dimethylacetamide (5 mL) 2-pyridine carboxaldehyde (0.082 g,

O, 764 mmol), sodium bisulfite (58.5%, 0.15 g, 0.84 mmol) and ptoluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150 ° C overnight. The mixture was cooled to room temperature. Water (40 ml) was added and the reaction mixture was extracted with dichloromethane (2x50 ml). The combined organic layers were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (silica gel, sieve number 230-400; 1% methanol in CH 2 Cl 2 as eluent) to give 5.7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one (0.077 g, 36%) as a white solid. 5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one was converted to the corresponding hydrochloride salt. Selected data: MS m / z: 284.0; MP 215-217 ° C (hydrochloride).

Reference example C [0177]

2070

2075

<img file="PL2118074T3_D0045.tif" />

5,7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one 5,7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) he was obtained from 2-amino-4.6-dimethoxybenzamide and 3-2-pyridinecarboxaldehyde, using the method described for reference example B. 5,7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one (105 mg, 48%) isolated as a white solid. Selected data: MS m / z: 284.0; MP 257-259 ° C (hydrochloride).

Example 31 [0179]

2080

<img file="PL2118074T3_D0046.tif" />

N- (2- (4- (5.7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2.6dimetylofenoksy) ethyl) -4-methoxy-benzamide

2085 [0180] According to the method described for reference example C, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in a yield of 46% and isolated it as a white solid. MS (APCI) m / z 526 [M + Na] +.

2090 Example 32 [0181]

<img file="PL2118074T3_D0047.tif" />

2095

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethylacetamide [0182] According to the method described for Example 27, the title compound

2100 made from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 40% yield and isolated as a white solid. MS (APCI) m / z 412 [M + H] +.

Example 33

2105 [0183]

<img file="PL2118074T3_D0048.tif" />

2110 N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide [0184] According to the method described for example 27, the title compound made from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,786 dimethoxyquinazolin-4 (3H) -one in 66% yield and isolated as

2115 white solid. MS (APCI) m / z 474 [M + H] +.

Example 34 [0185]

2120

<img file="PL2118074T3_D0049.tif" />

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -isobutyramide

2125 [0186] According to the method described for example 27, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 59% yield and was isolated as a white solid. MS (APCI) m / z 440 [M + H] +.

2130

Example 35 [0187]

2135

<img file="PL2118074T3_D0050.tif" />

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksv) ethyl) -3-methyl-urea

2140 [0188] A mixture of 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.10 g, 0.27 mmol), methyl isocyanate (0.020 g , 0.35 mmol) and Et3N (0.034 g, 0.35 mmol) in THF (4.0 mL) was stirred at room temperature for 16 hours. The mixture was filtered, washed with CH2Cl2 and the solvent removed under reduced pressure. Received

2145 the residue was purified by silica gel column chromatography to give the title compound (0.082 g, 71%) as a white solid. MS (APCI) m / z 449 [M + Na] +.

Example 36

2150 [0189]

<img file="PL2118074T3_D0051.tif" />

2155

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea [0190] According to by the method described for example 35, the title compound

2160 prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in 57% yield and isolated as a white solid. MS (APCI) m / z 541 [M + Na] +.

Example 37

2165 [0191]

<img file="PL2118074T3_D0052.tif" />

2170 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea [0192] According to the method described for example 35 , the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,72175 dimethoxyquinazolin-4 (3H) -one in a yield of 59% and was isolated as a light yellow solid. MS (APCI) m / z 489 [M + H] +.

Example 38

2180 [0193]

<img file="PL2118074T3_D0053.tif" />

3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,62185 dimethylphenoxy) ethyl) -1,1-dimethylurea [0194] According to the method described for example 35, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in a yield of 59% and was isolated as

2190 white solid. MS (APCI) m / z 441 [M + H1 +.

Example 39 (Reference example) [0195]

2195

<img file="PL2118074T3_D0054.tif" />

6,8-dimethoxy-3- (4-hydroxy-3,5-dimethylphenyl) -2H-1,2-benzothiazine-1,1-dioxide

2200 [0196] To a 3-necked round-bottomed flask, 3,5-dimethoxytoluene (6,088 g, 40 mmol) and cyclohexane (28 ml) were added under a nitrogen atmosphere. Dimethyl carbonate (30.3 g, 336 mmol) was added and the reaction mixture was heated at 60 ° C. Excess chlorosulfonic acid was added over 15 min. Freed

2205 HCl gas was removed by inserting the sodium hydroxide tube as a solid. After the addition was complete, the reaction mixture was heated to 70-72 ° C for 1 hour and then cooled to room temperature. The solid was filtered off and washed with a solution of dimethyl carbonate and cyclohexane (1: 1, 20 ml). The solid was dried in vacuo to give

2210 pure product (6.13 g. 66%). To the mixture of sulfonic acid (product from the above point, 4.65 g, 20 mmol) and triethylamine (2.03 g, 2.79 ml) in acetone (40 ml) was added 2,4,6-trichloro-1,3, 5-triazine (cyanuric chloride, 3.69 g, 20 mmol). The reaction mixture was heated to reflux for 20 hours, then cooled to room temperature. The solution was passed through a Celite pad and evaporated in vacuo to give a solid which was filtered off and washed with hexane. A mixture of the product and the cyanuric hydroxide salt and triethylamine (7.58 g) was used in the next step without further purification.

[0197] To a 3-necked round-bottom flask equipped with a condenser (cooling with dry ice and acetone) was added the mixture from the above step (7.58 g) and acetone (100 ml). The reaction mixture was cooled to -78 ° C and gaseous ammonia was bubbled through the solution for 0.5 h. The reaction mixture was held overnight, allowing slow evaporation of ammonia gas followed by evaporation of the solvent. Water was added and the product was extracted using DCM. The solvent was dried and evaporated to give a mixture of solid and thick liquid. The solid was filtered off and washed with hexane to give pure sulfonamide (3.23 g, 70%).

[0198] 3,5-dimethyl-4-hydroxybenzoic acid (2.99 g, 18 mmol) was added to the round bottom flask. Anhydrous DMF (20 mL) was added followed by sodium hydride (1.8 g, 45 mmol). The reaction mixture was stirred at room temperature for 1 hour. P-methoxybenzyl chloride (6.20 g, 39.6 mmol) was added and the reaction mixture was stirred at room temperature overnight (~ 20 hours). The reaction mixture was poured into water, acidified with 1 N HCl and stirred for 1 h. The precipitated solid was filtered off, washed with water and hexane to give a pure block forming ring B (6.93 g, 95%). [0199] Block forming ring B (6.93 g, 17.1 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL). Potassium hydroxide (1.25 g, 22.2 mmol) in water (20 ml) was added. The reaction mixture was heated to reflux at 70 ° C for 24 hours. The solvent was evaporated in vacuo. Water was added and the reaction mixture was acidified with 1 N HCl (pH 4-5). The solid was filtered off and washed with water and hexane. The yield was 4.61 g (94%). The product (1.932 g, 6.75 mmol) and sulfonamide from above (1.04 g, 4.5 mmol) were placed in a 3-necked round-bottom flask under a nitrogen atmosphere. Dichloromethane (100 mL) was added with stirring. To this stirred mixture, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) was added. HCl, 1.36 g, 7.09 mmol) followed by N, N-dimethylaminopyridine (2.06 g, 16.9 mmol). The reaction mixture was stirred at room temperature for 24 hours, then washed with 1 N HCl, 2.5% NaOH and saturated sodium bicarbonate. The organic layers were dried and evaporated in vacuo to give a residue which was purified by silica gel column chromatography (100 g) using 2050% ethyl acetate in hexane and 5% methanol in dichloromethane as eluents. Fractions 30-66 were combined to give a pure product (1.35 g, 60%). The compound of the above step (0.105 g, 0.21 mmol) was dissolved in tetrahydrofuran under a nitrogen atmosphere and cooled to -78 ° C. N-butyllithium was added and the reaction mixture was allowed to warm slowly to room temperature and stirred overnight (~ 14h). Thin layer chromatography (TLC) showed incomplete conversion. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent was evaporated in vacuo to give a residue which was purified by silica gel column chromatography (15 g) using 20-50% ethyl acetate in hexane as eluent. The product was not pure enough, another column was used, using 0.5% methanol in hexane as the eluent, and finally preparative thin layer chromatography was used to purify the product. The compound of the above step (0.277 g) was dissolved in trifluoroacetic acid (10 ml) under a nitrogen atmosphere and the reaction mixture was heated to reflux (bath temperature 80 ° C) for 4 days. The solvent was evaporated in vacuo and the residue was dissolved in 0.25 N NaOH (20 ml) and acidified with acetic acid. A solid precipitated at this point. The solid was filtered off and washed with water and hexane and dried. 0.005 g of pure product was recovered from one batch. 0.060 g of compound was isolated from another batch, which was not pure enough. This compound was further purified by preparative high performance liquid chromatography (HPLC),

2275 to obtain pure 6,8-dimethoxy-3-4-hydroxy-3,5-dimethylphenyl) -2H-1,2-benzothiazine-1,1-dioxide (0.010 g). Selected data: MP 246.6-247.4 ° C.

Example 40 (Reference example)

2280 [0200]

<img file="PL2118074T3_D0055.tif" />

- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-7 2285 (morpholinomethyl) isoquinolin-1 (2H) -one [0201] Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 ml) was cooled to -5 ° C and sodium hydride in mineral oil (24.5 g, 60%) was added at a temperature from -5 to 0 ° C over 30 min. Diketon (50.4 g) in dry THF (80

2290 ml) was added dropwise at 5 ° C over 20 min. The resulting solution was allowed to continue stirring for 1 hour. at -5 ° C, then allowed to warm to room temperature and stirred overnight. Acetic acid (35 ml) was added and the THF solvent removed. Water (200 ml) and ethyl acetate (300 ml) were added to the residue and the pH was adjusted to 5.0

2295 by adding HCl solution. The organic layer was separated, washed with brine and dried over sodium sulfate. Purification by column chromatography and recrystallization gave compound A (26.6 g, 24.3%).

[0202] Sodium hydride in mineral oil (11.2 g, 0.279 mol, 60%) was added to compound A (24.8 g, 0.136 mol) in DMF (150 ml). Reaction mixture

2300 cooled to -30 ° C, methyl iodide (21.3 mL, 0.341 mol) was added and the reaction mixture was kept at room temperature overnight. Sodium iodide was filtered off and DMF removed. The residue was mixed with water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude mixture was purified by column chromatography to afford compound B (11.40 g, 39.9%). To a solution of compound B (11.4 g, 0.054 mol) in dry CCl4 (90 ml) was added N-bromosuccinimide (10.6 g,

0.0596 mol). The mixture was heated to reflux overnight and the solvent CCl4 was removed. Water (100 ml) was added to the residue. After stirring for a while, the solid was filtered off and washed with water, ethyl acetate (10 mL) and hexane (30 mL) to give the compound (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethyl methyl ether (81.0 g) and anhydrous chloride (7.0 g, 0.051 mol) was kept at room temperature overnight. The chloromethylmethyl ether was removed and the residue was mixed with water and the pH was adjusted to 7.0 with sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Column chromatography gave compound D (7.39 g, 50.6%). A solution of compound D (7.39 g, 0.022 mol), morpholin (7.62 g, 0.088 mol) and anhydrous THF (20 ml) was kept at room temperature overnight. The solvent was evaporated.

Water and ethyl acetate were added to the residue, and the pH was adjusted to 9.0 with sodium bicarbonate. The organic layer was washed with brine and dried over sodium sulfate, and then concentrated. Column chromatography gave compound E (5.4 g, 63.8%). The hydrogenation reaction was carried out at 50 psi using compound E (5.4 g, 0.014 mol) in THF (100 ml) and triethylamine (3.9 ml) with 10% carbon-supported palladium (2.6 g) as a catalyst in within 2 days. After filtering off the catalyst, the organic layer was purified by column chromatography to give product F (3.20 g, 74.4%). Compound F (3.20 g, 0.0103 mol) was dissolved in ethanol (30 ml) and potassium hydroxide (2.31 g, 0.041 mol) in water (20 ml) was added and the reaction mixture was heated to 100 ° C overnight . The solvent was removed, the pH was adjusted to 6.0 and water was removed. The residue was further dried under high vacuum and the compound was extracted with ethanol to give compound G (2.95 g, 99%). Compound G (1.80 g, 6.1 mmol) with thionyl chloride (3 mL, 0.0411 mol) was heated to reflux for 1 h, after which excess thionyl chloride was removed and the residue was dried under high vacuum. Anhydrous THF (20 mL) was added and gaseous ammonia was bubbled into the reaction mixture for 2 hours. THF was removed and the pH was adjusted to 8.0-9.0. The mixture was extracted with dichloromethane and dried over sodium sulfate to give compound H (1.30 g, 72.4%).

[0203] NaH in mineral oil (1.14 g, 0.0285 mol, 60%) was added to 4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF (20 ml), followed by the addition of benzyl bromide (3.27 mL, 0.027 mol). The reaction mixture was kept at room temperature overnight. The reaction mixture was poured into water and the solid was filtered off and washed with hexane to give compound I (5.7 g, 89%). Compound I was used in the next reaction step without further purification. BuLi (1.60 M, 10.2 mL) was added dropwise to Compound H (0.8 g, 2.72 mmol) in anhydrous THF (25 mL) at -10 ° C. The reaction mixture was kept at 0 ° C for one hour, after which the cooling bath was removed. The reaction mixture was stirred for 45 min. Compound I (0.65 g, 2.72 mmol) in anhydrous THF (5 mL) was added dropwise at 10 ° C and the reaction continued for another 45 min. Water (20 ml) was added. The mixture was extracted with ethyl acetate. The solvent was removed and the residue was purified by column chromatography to give compound J (0.180 g, 12.8%). Compound J (180 mg) in methanol (80 ml) was hydrogenated at 50 psi for 3 hours using 10% palladium on carbon as a catalyst. The catalyst and solvent were removed and the residue was purified by column chromatography to give 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-7- (morpholinomethyl) -isoquinolin1 (2H) -one (28 mg, 18.8% ) as a white solid. Selected data: MS m / z: 424.21; MP 158-161 ° C.

Example 41: Quantification of ApoA-I at the mRNA level [0204] In this example, ApoA-I at the mRNA level in tissue culture cells was quantified to measure the increase in transcriptional regulation of ApoA-I when the compound of the present invention was administered.

[0205] HepG2 cells (~ 2x10⁵ per well) was placed in a 24-well plate in ~ 400 μL MEM with the addition of 0.5% (v / v) fetal bovine serum (FBS), 24 hours before adding the compound. At the time of separation, the medium used was removed from HepG2 cells and immediately placed on ice (for direct use) or at -80 ° C (for future use) in ApoA-I and using albumin ELISA. The cells remaining in the wells of the plate were washed in 200 μL of buffered saline (PBS). PBS was carefully removed to avoid the removal of any loosely attached cells.

[0206] After removal of PBS, 85 μL cell disintegration solution was added to the cells in each well and incubated for 5-10 min. at room temperature to ensure complete breakdown and detachment of the cells. Then mRNA was prepared using the "Catcher PLUS mRNA plate" from Invitrogen according to the provided protocol. After the last wash, the largest possible amount of wash buffer was aspirated, not allowing the wells to dry. Then, elution buffer (E3, 80 μΐ) was added to each well, after which the mRNA was eluted by incubating the Catcher PLUS mRNA plate with elution buffer for 5 min. at 68 ° C and then immediately put the plate on ice.

[0207] The isolated eluted mRNA was then used in a single-step polymerase chain reaction (PCR) in real time at room temperature, using Ultra Sense Kit components and Applied Biosystems primers and probes. Real-time PCR data was analyzed using the Ct value to determine the induction fold of each unknown sample relative to the control sample (i.e., the control sample of each independent DMSO concentration).

[0208] An active compound is one that causes&gt; 15% increase in ApoA-I on

2395 mRNA level at a concentration less than or equal to 100 μΜ.

<td>No. example</td><td>Relationship Name</td><td>Impact on ApoA-I at the mRNA level</td>

<td> 38</td><td>3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethyl urea</td><td>Active</td>

<td> 37</td><td>1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -3-phenyl-urea</td><td>Active</td>

<td> 36</td><td>1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -3- (4-methoxyphenyl) urea</td><td>Active</td>

<td> 35</td><td>1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -3-methyl-urea</td><td>Active</td>

<td> 34</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -isobutyramide</td><td>Active</td>

<td> 33</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) benzamide</td><td>Active</td>

<td> 32</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) acetamide</td><td>Active</td>

<td> 31</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) methoxybenzamide</td><td>Active</td>

<td> 30</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -4metylobenzenosulfonamid</td><td>Active</td>

<td> 29</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) benzenesulfonamide</td><td>Active</td>

<td> 28</td><td>2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate</td><td>Active</td>

<td> 27</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -4-methyl-benzamide</td><td>Active</td>

<td> 26</td><td>2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate</td><td>Active</td>

<td> 25</td><td>2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl propylcarbamate</td><td>Active</td>

<td> 24</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) methanesulfonamide</td><td>Active</td>

<td> 23</td><td>4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) benzenesulfonamide</td><td>Active</td>

<td> 22</td><td>N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -4metoksybenzenosulfonamid</td><td>Active</td>

<td> 21</td><td>N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-</td><td>Active</td>

<td></td><td>dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -N2-metyloftalamid</td><td></td>

<td> 20</td><td>4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) benzenesulfonamide</td><td>Active</td>

<td> 18</td><td>2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 18</td><td>N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6dimetylofenoksy) ethyl) -N2-metyloftalamid</td><td>Active</td>

<td> 17</td><td>2- (4-amino-3,5-dimethylphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 16</td><td>5,7-dimethoxy-2- (4-m ethoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one</td><td>Active</td>

<td> 15</td><td>2- (2-chloro-6-methyl-pyridin-4-yl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 14</td><td>2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7dimetoksypirydo [2,3-d] pyrimidin-4 (3H) -one</td><td>Active</td>

<td> 13</td><td>2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 12</td><td>2- (2,3-dihydro-benzo [b1 [1,41dioksyn-6-yl) -6,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 11</td><td>2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 10</td><td>2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 9</td><td>2- (4-hydroxy-3-methoxyphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 8*</td><td>3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-</td><td>Active</td>

<td></td><td>1 (2H) -one</td><td></td>

<td> 7</td><td>2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td>Active</td>

<td> 6*</td><td>7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-natrifridin-5 (6H) -one</td><td>Active</td>

<td> 5*</td><td>3- (4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinoline-1 (2H) -one</td><td>Active</td>

<td> 4</td><td>2- (4-hydroxy-3,5-dimethylphenyl) -5.7 dimethoxyquinazolin-4 (3H) -one</td><td>Active</td>

<td> 3*</td><td>3- (4-hydroxy-3,5-dimethylphenyl) -7 (morpholinomethyl) isoquinolin-1 (2H) -one</td><td>Active</td>

<td> 2*</td><td>3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8dimetoksyizochinolin-1 (2H) -one</td><td>Active</td>

<td> 1*</td><td>3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one</td><td>Active</td>

<td colspan="3">* Reference example</td>

Example 42: ApoA-I at mRNA level and protein induction

2400 [0209] In this example, ApoA-I was quantified at mRNA level and protein secreted from tissue culture cells. The test can be used to determine the potency of compounds of interest, including those of the present invention.

[0210] HepG2 cells and primary human hepatocytes (BD Gentest, series 107)

2405 (~ 2x10⁵ per well) was placed in a 24-well plate in ~ 400 μΐ MEM with the addition of 0.5% (v / v) fetal bovine serum (FBS), 24 hours before adding the compound. Compounds of interest were dissolved in DMSO at a concentration of 0.05% (v / v). Then the appropriate volumes of stock solutions in DMSO were added to the appropriate volumes of MEM from

100 by adding 0.5% (v / v) FBS to obtain the desired concentration (for example, 1 uL of the basic compound to 1 ml MEM, with the addition of 0.5% (v / v) FBS).

[0211] Immediately before adding the compound to the cells, the culture medium was aspirated and replaced with 300 µL of fresh MEM, with the addition of 0.5% (v / v) FBS, followed by 300 µL. the compound of interest in MEM, with the addition of 0.5% (v / v) FBS, to achieve the desired final concentration of the compound in a total volume of 600 μϋ. The final diluent concentration (DMSO) was 0.05% (v / v).

[0212] Cells were incubated for the desired time. The cell medium was then harvested, as were the cells. ApoA-I at the mRNA level was measured as described in Example 39. Secreted ApoA-I was measured by the ApoA-I ELISA as described below.

ApoA-I ELISA [0213] In this example, ApoA-I secreted into the medium from tissue culture cells was quantified to assess the induction of endogenous ApoA-I protein secretion from cells treated with various small molecule compounds such as those of the present invention.

[0214] At the time of separation, the medium used from HepG2 cell culture or from primary cell culture was removed and stored at 80 ° C in 1.5 ml microtiter tubes.

[0215] For the ELISA test for human ApoA-I, the ELISA plate was coated with ~ 100 μϋ / well of human ApoA-I capture antibody diluted to ~ 2 µg / mL in coating buffer over ~ 1 hour. in room temperature. The plate was then washed three times with washing buffer. Then, the plate was blocked with ~ 200 µL / well of human ApoA-I blocking buffer for at least ~ 30 min. in room temperature.

[0216] Samples to be used to generate the standard curve were obtained from the medium used (MEM, with the addition of 0.5% (v / v) FBS) from

101 HepG2 cells or primary cells treated with DMSO for 48 hours. Serial 2-fold dilutions of medium were performed in MEM, with addition of 0.5% (v / v) FBS. Unknown samples, derived from cultures treated with compounds of interest, also

2445 diluted in MEM with the addition of 0.5% (v / v) FBS. The plate was washed three times in washing buffer. A standard curve and unknown samples (100 μΐ / well) were added to the plate in triplicate and the plate was incubated for 1.5 hours. in room temperature.

[0217] The plate was washed three times in washing buffer. Added

2450 human ApoA-I detection antibody, diluted 1: 1000 in PBS, (100 μΐ / well), and the plate incubated for 1 hour. in room temperature. The plate was washed three times in washing buffer.

[0218] Goat conjugate against rabbit IgG H antibodies and chain specific per peroxidase conjugate, diluted in ratio were added

2455 1: 2000 in PBS, (100 μΐ / well), and the plate incubated for 40 min. at room temperature in the dark. The plate was washed six times in wash buffer.

[0219] TMB liquid substrate (100 μΐ / well) was added and the plate was incubated on a shaker under aluminum foil during development. After reaching enough

2460 "blue" color, stopping solution (50 μΐ / well, 1 M H2SO4) was added and mixed thoroughly on a plate shaker. Air bubbles were removed and absorbance at 450 nm was determined using Molecular Devices SpectraMax 190 Plate Reader and Softmax ELISA software related to human ApoA-I.

2465

<td>No. example</td><td>Relationship Name</td><td>Protein EC50 ^ M)</td>

<td> 20</td><td>4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydrochinazolin2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide</td><td> 0,32</td>

102

<td> 18</td><td>2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td> 7,22</td>

<td> 18</td><td>N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethyl-phenoxy) ethyl) -N2-metyloftalamid</td><td> 7,29</td>

<td> 17</td><td>2- (4-amino-3,5-dimethylphenyl) -5,7-dimetoksychinazolin4 (3H) -one</td><td> 7,63</td>

<td> 16</td><td>5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin4 (3H) -one</td><td> 16,46</td>

<td> 15</td><td>2- (2-chloro-6-metviopirydvn-4-vio) -5,7-dimetoksvchinazoiin4 (3H) -one</td><td> 3,96</td>

<td> 14</td><td>2- (4- (2-hydroxvetoxyl) -3,5-dimethylphenyl) -5,7-dimethoxylated to 2,3-d | pyridimnn-4 (3I I) -one</td><td> 9,20</td>

<td> 13</td><td>2 - (- 4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td> 13,72</td>

<td> 12</td><td>2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7dimetoksychinazolin-4 (3H) -one</td><td> 9,07</td>

<td> 11</td><td>2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7dimetoksychinazolin-4 (3H) -one</td><td> 13,30</td>

<td> 10</td><td>2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td> 12,11</td>

<td> 9</td><td>2- (4-hydroxy-3-methoxyphenyl) -5,7-dimetoksvchinazolin4 (3H) -one</td><td> 12,08</td>

<td> 8*</td><td>3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) 6,8-dimethoxyisoquinolin-1 (2H) -one</td><td> 2,82</td>

<td> 7</td><td>2- (4- (2-hydroksvetoksv) -3,5-dimethylphenyl) -5,7dimetoksychinazolin-4 (3H) -one</td><td> 12,16</td>

<td> 6*</td><td>7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6natfyrydyn-5 (6H) -one</td><td> 6,52</td>

<td> 5*</td><td>3- (4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one</td><td> 6,27</td>

103

<td> 4</td><td>2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimetoksychinazolin4 (3H) -one</td><td> 7,93</td>

<td> 3*</td><td>3- (4-hydroxy-3,5-dimethylphenyl) -7 (morpholinomethyl) isoquinolin-1 (2H) -one</td><td> 11,09</td>

<td> 2*</td><td>3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one</td><td> 11,35</td>

<td> 1*</td><td>3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimetoksyizochinolin1 (2H) -one</td><td> 5,42</td>

<td></td><td>2- (4-hydroxyphenyl) pyrano [2,3-b] pyridin-4-one</td><td> 179,47</td>

<td colspan="3">* Reference example</td>

EXAMPLE 43: In vivo efficacy [0220] To test if the efficacy of the compounds of the present

2470 of the invention observed in vitro, extends to an in vivo model, transgenic mice carrying multiple copies of the human ApoA-I gene (Bisaha et al. (1995) J. Biol. Chem. 34, 19979-88) or wild-type mice (C57BL / 6 (Stock Number 000664) Jackson Laboratory (Bar Harbor, ME) was treated with the compounds of the present invention. In the case of mice

2475 transgenic, exogenous human ApoA-I gene in these mice enables them to express human ApoA-1 protein under the control of their own promoter. [0221] Male mice from seven to eight weeks old were housed five in a cage (10 "x20" x8 "on aspen shavings) giving them granulated rodent feed [Purina 5001] and ensuring access to water at all times.

2480 After an air-conditioning period of 1 week, the animals were individually identified by affixing the tail number and weighed. The mice were initially induced extraocular bleeding and 100 μΐ blood collected in a 1.5 ml Eppendorf tube containing 5 μΐ 0.5 mM EDTA and cooled on ice. Plasma was collected after centrifugation of whole blood at 14,000 rpm [high speed]

2485 TOMY NTX-150] microcooling centrifuge for 10 min. at 4 ° C

104 and frozen at -80 ° C. The mice were grouped based on an average body weight of 25 g.

[0222] The day after the initial blood sampling, mice were dosed by oral gavage or by intraperitoneal administration daily with a single dose.

2490 feeding needles with 20 gauge and 11/2 "curvature (Popper &amp; Sons): for mice fed twice daily (BID) - the dose was administered by oral gavage in the morning and afternoon (at 8:00 and 17:00); for mice fed once daily (QD) - the dose was administered in the morning (at 8:00 am) Compounds were prepared each day in vehicle. One day before

2495 the autopsy was weighed and left without food overnight. On the last day of dosing, mice were sacrificed after 2 hours. from dosing by inhalation of CO2 and blood was taken by cardiac puncture (0.7-1.0 ml). Plasma was collected and frozen at -80 ° C. Samples were tested for ApoA-I by ELISA and HDL-C for

2500 High Performance Liquid Chromatography (HPLC) (Polaris 200 with Varian Prostar 410 automatic sampler on Amersham 10/30 Superose 6 column). During autopsy, liver and duodenal enterocytes as well as jejunum of the small intestine were collected, purified with cold PBS and frozen at -80 ° C for further compound and level analysis

2505 mRNA by Q-PCR.

[0223] Experiment A 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (10, 30 and 60 mg / kg body weight, mpk) was administered twice daily hApoA-I transgenic mice daily for seven days by oral gavage in 1% DMSO, 2.5% Tween-80, 10% PEG-300

2510 QS to water. Plasma was tested for ApoA-I (Fig. 1) and HDL cholesterol (Fig. 2).

[0224] Experiment B 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (10, 30 and 60 mg / kg body weight) was administered twice daily C57BL / 6 wild-type mice daily for three days

2515 intraperitoneal in 1% DMSO, 2.5% Tween-80, 10% PEG-300 QS to water. Plasma was examined for ApoA-I (Fig. 3) and HDL cholesterol (Fig. 4).

105 [0225] The C 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one experiment (30 mg / kg body weight) was administered twice daily to hApoA- transgenic mice And every day for seven days using

2520 oral tube in 1% DMSO, 2.5% Tween-80, 10% PEG-300 QS for water. Plasma was examined for ApoA-I and tissues for mRNA (Fig. 5).

[0226] These results indicate that the compounds of the present invention are useful for increasing ApoA-I transcription in vivo and increasing plasma ApoA-I and HDL-C levels in circulating blood in

2525 wild-type and hApoA-I transgenic mice. These results indicate that the compounds of the present invention activate the ApoA-I transgene in mice, which leads to an increase in ApoA-I in circulating blood.

[0227] All references mentioned herein are incorporated by reference in their entirety. Other embodiments of the invention will be

2530 obvious to those skilled in the art from reading the description and practice of the invention disclosed herein. It is intended that the description and examples be taken as exemplary only, indicating the true scope and spirit of the invention in the following claims.

106